BRPI0816144B1 - SOLID PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION, ITS USE AND METHOD FOR PREPARING SAID COMPOSITION - Google Patents

Abstract

SOLID PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION, USE THEREOF, AND METHOD FOR PREPARING SAID COMPOSITION. The present invention relates to pharmaceutical compositions and methods for treating neoplastic disease comprising the combination of a taxane, such as docetaxel, with a CYP3A4 inhibitor, such as ritonavir. Methods of treating neoplastic disease incorporating the administration of a taxane and the administration of a CYP3A4 inhibitor, either simultaneously or separately, are also included. Furthermore, kits for carrying out the methods are included. Solid pharmaceutical taxane compositions for oral administration comprising a substantially amorphous taxane, a carrier, and a surfactant are also included.

Description

[0001] The present invention relates to pharmaceutical compositions. In particular, although not exclusively, it relates to compositions and methods for the treatment of neoplastic disease.

[0002] Oral drug administration offers a number of advantages. The availability of an oral anticancer drug is important when treatment must be administered chronically to be optimally effective, for example, 5-fluorouracil (5-FU) prodrugs (e.g., capecitabine) and drugs that interfere with signal transduction pathways or the angiogenesis process [1]. Furthermore, oral drugs can be administered on an outpatient basis or at home, increasing patient convenience and quality of life and possibly decreasing costs by reducing hospital admissions [2]. Therefore, it is advantageous to attempt to administer anticancer drugs orally.

[0003] In general, oral administration of drugs is convenient and practical. However, most anticancer drugs unfortunately have low and variable oral bioavailability [1]. Typical examples are the widely used taxanes, docetaxel and paclitaxel, which have an oral bioavailability of less than 10% [3, 4]. Several other anticancer agents with higher bioavailability demonstrate greater variability. Examples include topoisomerase I inhibitors, the vinca alkaloids, and mitoxantrone [1, 5, 6]. Given the narrow therapeutic window, variable bioavailability can result in unanticipated toxicity or decreased efficacy when therapeutic plasma levels are not achieved. Hellriegel et al. demonstrated in one study that plasma levels after oral administration are generally more variable than after i.v. administration [7]. Adequate oral bioavailability is important when the period of drug exposure is a major determinant of anticancer therapy [8]. Adequate oral bioavailability is also important to prevent high local drug concentrations in the gastrointestinal tract that can cause local toxicity.

[0004] Chen et al. [95] conducted experiments to try to enhance the solubility of the anticancer drug docetaxel in order to improve its bioavailability. Chen et al. attempted to use solid dispersions of docetaxel with various carriers, namely, glyceryl monostearate, PVP-K30, or poloxamer 188. Chen et al. found that poloxamer 188 increased the solubility of docetaxel to about 3.3 Qg/ml after 20 minutes (in a standard dissolution test) and to a maximum of about 5.5 Qg/ml after about 120 minutes when a docetaxel to poloxamer ratio of 5:95 was used. PVP-K30 increased the solubility of docetaxel only to about 0.8 Qg/ml after 20 minutes and to a maximum of 4.2 Qg/ml after about 300 minutes. Glycerol monostearate hardly increased the solubility of docetaxel overall. Thus, the solubility and dissolution rate of docetaxel were not increased to a particularly high level.

[0005] There are a number of important mechanisms that may explain the variable and/or low oral bioavailability of anticancer drugs, such as high affinity for drug transporters in the gastrointestinal tract, which limits absorption, and high drug extraction by extensive metabolism in the intestine and/or liver (first-pass effect) [1, 4, 9]. Other important factors include structural instability and limited solubility of the drug in gastrointestinal fluids, drug-drug and drug-food interactions, motility disorders, obstructive disorders, the presence of nausea and vomiting, or local toxicity in the gastrointestinal tract.

[0006] Regarding drug transporters and metabolic enzymes affecting the bioavailability of oral drugs, it has been speculated that the main drug transporters and metabolic enzymes responsible for the low/variable oral bioavailability of anticancer drugs are P-glycoprotein (P-gp) and cytochrome P450 (CYP) isoenzymes.

[0007] P-glycoprotein (P-gp) is a membrane-bound multidrug transporter that functions as an efflux pump or energy-dependent transport to decrease intracellular drug accumulation by exporting xenobiotics from the cell. P-gp has been identified in normal tissues with an excretory function, such as the bile canalicular membrane of hepatocytes, the luminal membrane of endothelial cells in the blood-brain barrier and the blood-testis barrier, the apical membrane of placental syncytial trophoblasts, the apical epithelial membrane of the intestine, and the renal proximal tubules. P-gp has an important barrier function in protecting tissues against xenotoxins [9-12].

[0008] P-gp is believed to prevent certain pharmaceutical compounds from crossing the mucosal cells of the small intestine and therefore from being absorbed into the systemic circulation. A wide range of drugs with varying physicochemical characteristics and pharmacological activity, such as verapamil, quinidine, and cyclosporine A (CsA), and the novel active blockers GF120918 (elacridar), LY335979 (zosuquidar), and R101933, have been shown in clinical studies to modulate P-gp [13-18]. Mechanisms by which P-gp modulators may influence anticancer drug pharmacokinetics after i.v. administration are competition for intestinal or hepatic cytochrome P450 (CYP)-mediated metabolism, inhibition of P-gp-mediated biliary excretion, intestinal transport, and inhibition of renal elimination [19, 20]. Only a few prospective randomized studies combining an anticancer agent with or without a modulator have been performed. These studies revealed that dose reductions of the anticancer drug, when combined with a modulator, were necessary to prevent severe drug-related toxicity. Furthermore, these studies did not show any survival benefit from combining an anticancer drug with a modulator [21-23].

[0009] For many anticancer drugs, cytochrome P450 (CYP) is the major enzyme system of oxidative drug metabolism. CYP isozymes are highly expressed in the liver and intestine, but the exact contribution of each isozyme to drug metabolism is unknown. It is recognized that intestinal extraction by this enzyme system plays an important role in limiting the oral bioavailability of drugs [31]. Humans have four identified functional CYP34 enzymes, which are the predominant drug-metabolizing enzymes and account for approximately 30% of hepatic CYP expression and over 70% of intestinal CYP [24, 30, 32, 33].

[00010] Some P-gp modulators also appear to be substrates for CYP3A, an isoenzyme of the CYP system. The overlap in substrate selectivity for P-gp and CYP3A, combined with their tissue localization, suggests that these two proteins cooperate and constitute an absorption barrier against toxic xenobiotics [24-26]. Cummins et al. confirmed this and showed that P-gp can affect intestinal drug metabolism (especially the CYP3A4 isoenzyme) by controlling a drug's access to the intracellular metabolizing enzyme system [27]. Therefore, it appears that P-gp and CYP3A may play a role in the limited and/or variable oral bioavailability of shared-substrate drugs in the intestine.

[00011] The taxanes paclitaxel and docetaxel have proven anticancer activity in many tumor types (e.g., breast, ovarian, head and neck cancer, and non-small cell lung cancer [NSCLC]). Currently, the drugs are administered intravenously in different dosages and regimens [34]. However, in oral formulations, taxanes have very low oral bioavailability. This is speculated to be due to the action of P-gp and CYP3A. Studies attempting to increase the bioavailability of orally administered drugs have been performed in mice and humans with several anticancer drugs (e.g., taxanes).

[00012] When paclitaxel is administered orally, bioavailability is very low (<10%). This is caused by the high affinity of paclitaxel for P-gp, which is present in the gastrointestinal tract [4, 10, 35, 36]. Furthermore, presystemic clearance in the gut wall and liver by CYP 3A4 and 2C8 isoenzymes may also play a role in the low oral bioavailability of paclitaxel [37-39]. Recent studies with wild-type and P-gp mdr1a null mice have shown unequivocally that P-gp limits paclitaxel absorption. In a proof-of-concept study in null mice compared with wild-type mice, investigators demonstrated a six-fold and two-fold increase in the area under the plasma concentration-time curve (AUC) of paclitaxel after oral and i.v. administration, respectively [4]. The fraction of unchanged paclitaxel recovered from the feces of wild-type mice after oral administration was 87% of the dose compared with 3% in P-gp mdr1a knockout mice. Despite complete absorption from the gastrointestinal tract, bioavailability does not increase to 100%, likely due to first-pass intestinal/hepatic extraction [4, 40].

[00013] Based on this observation, several new studies were initiated with P-gp inhibitors in combination with paclitaxel in order to enhance oral bioavailability. Studies in mice revealed that co-administration of SDZ PSC833, a cyclosporine D analog and potent P-gp inhibitor, with paclitaxel resulted in a 10-fold increase in systemic exposure [41]. A similar study was performed with CsA and paclitaxel, which showed comparable effects [42]. Oral bioavailability in wild-type mice increased from 9% to 67% when CsA was co-administered. It was also noted that the plasma levels of paclitaxel obtained in wild-type mice co-treated with CsA were even higher than those obtained in null mice that were treated with oral paclitaxel without CsA. This can be explained by increased uptake through inhibition of P-gp in the gastrointestinal tract and decreased elimination through inhibition of CYP3A [42-45]. However, blockade of other as yet unidentified drug transporters or drug elimination pathways cannot be excluded.

[00014] Long-term oral dosing of CsA has been associated with immunosuppressive effects that are detrimental to individual health. Therefore, an alternative, the non-immunosuppressive P-gp blocker GF120918, has been explored to enhance the oral bioavailability of paclitaxel. GF120918 was developed primarily to reverse P-gp-mediated multidrug resistance in tumors [16]. In a recently published study, Bardelmeijer et al. demonstrated that GF120918 significantly increased the oral bioavailability of paclitaxel [46]. The oral bioavailability of paclitaxel in wild-type mice increased from 8.5% to 40%, and the pharmacokinetics of paclitaxel in wild-type mice given GF120918 were similar to those found in mdr1a/b P-gp null mice. Thus, GF120918 effectively blocks P-gp in the intestine and, most likely, does not interfere with other pathways involved in paclitaxel uptake or elimination. For the record, GF120918 was recently shown to also be an effective inhibitor of the ABS drug transporter BCRP (ABCG2) [28, 29].

[00015] Docetaxel is also a P-gp substrate, first shown in 1994 by Wils et al. [47, 48]. Because of the encouraging results obtained with paclitaxel in combination with P-gp inhibitors, mouse studies were also performed with docetaxel. These studies confirmed that P-gp also plays an important role in the low bioavailability of docetaxel. The AUC of oral docetaxel increased ninefold by co-administration with CsA [49]. Furthermore, co-administration of ritonavir, a CYP3A4 inhibitor with minimal P-gp inhibition properties, was tested in mice. CYP3A4 is the main enzyme responsible for the metabolic breakdown of docetaxel in humans [50]. The inventors performed preclinical studies in mice in which ritonavir was co-administered with docetaxel and showed an increase in evident bioavailability from 4% to 185%. Extensive first-pass metabolism could also contribute greatly to the low bioavailability of oral docetaxel in mice [49]. Cytochrome P450 enzymes in the mouse intestine (referred to as Cyp) are different from those found in humans and have different substrate specificities. Furthermore, the regulation of CYP expression between mice and humans differs considerably due to differences in the activity, expression, and regulation of transcription factors, e.g., PXR for human CYP3A [88–92]. Therefore, these mouse studies cannot be relied upon to provide any indication of the results in humans, since the physiology, enzymes, etc. of mice are completely different from those of humans. Consequently, the mouse data cannot be simply extrapolated to humans. Furthermore, this mouse study used an extremely high dose of docetaxel (10–30 mg/kg), which could be lethal in humans, and also a high dose of ritonavir (12.5 mg/kg). For a 72 kg individual, this would mean 720–2160 mg of docetaxel. However, patients are not usually treated clinically with docetaxel doses between 100 and 200 mg (intravenously). Clearly, due to the high drug levels administered, this approach is not feasible in humans. Furthermore, mouse data provide no evidence regarding the safety of the oral approach with this combination in humans.

[00016] Based on extensive preclinical studies in mice, several clinical proof-of-concept studies have been initiated. Patients with solid tumors received a course of 60 mg/m2 oral paclitaxel as a single agent or 60 mg/m2 oral paclitaxel in combination with 15 mg/kg CsA. Co-administration of oral CsA resulted in an eight-fold increase in systemic exposure to oral paclitaxel, and the apparent bioavailability of oral paclitaxel in this study increased from 4% without CsA to 47% with CsA [3]. This increase in systemic exposure was most likely caused by inhibition of P-gp in the gastrointestinal tract, but inhibition of paclitaxel metabolism may also have contributed to the effect, as concluded from preclinical studies [41, 42]. In order to further increase the systemic exposure of paclitaxel, a dose-escalation study with oral paclitaxel in combination with CsA revealed that the maximum tolerated dose was 300 mg/m2 and the increase in AUC at the higher doses was not dose-proportional [52]. At this higher dose level, a mass balance study was performed to measure fecal excretion. At the highest dose level of 300 mg/m2, total fecal excretion was 76%, 61% of which was parent drug, which may be explained by the incomplete absorption of orally administered paclitaxel from the gastrointestinal tract [53]. It has been speculated that the high amount of the co-solvent Cremophor EL in the i.v. paclitaxel formulations used for oral administration prevented the complete absorption of orally applied paclitaxel. Furthermore, Cremophor EL, which is responsible for the nonlinear pharmacokinetics of i.v. paclitaxel and severe hypersensitivity reactions, was not absorbed after oral paclitaxel administration, since plasma levels of Cremophor EL were not detected [54–56]. This may be an additional advantage of oral paclitaxel administration [51, 52]. Subsequently, in order to increase the duration of systemic exposure of oral paclitaxel above a threshold level of 0.1 M, a twice-daily (b.i.d.) dosing regimen of oral paclitaxel in combination with CsA was explored in patients. At the 2 × 90 mg/m2 dose level, adequately long-lasting systemic exposure of paclitaxel above the 0.1 M level was achieved with a good safety profile [57]. In these studies, patients orally ingested the intravenous paclitaxel formulation (also containing Cremophor EL and ethanol) [57]. Additionally, a dose-finding study of oral paclitaxel with CsA showed that P-gp inhibition by CsA was maximal at a single dose of 10 mg/kg [58].

[00017] In another phase I study, patients received 1,000 mg GF120918 1 hour before oral paclitaxel [59]. The increase in systemic exposure to paclitaxel was of the same magnitude as in the combination with CsA. Based on the results of these phase I studies, phase II studies were initiated to investigate whether repeated oral administration of paclitaxel was feasible and active. Oral paclitaxel was given b.i.d. once weekly in several tumor types: a first- and second-line treatment in NSCLC [60], as first-line treatment in advanced gastric cancer [99], and as a second-line treatment in advanced breast cancer [100]. All patients were treated with oral paclitaxel weekly b.i.d. at a dose of 90 mg/m2. CsA, at a dose of 10 mg/kg, was given 30 minutes before each paclitaxel dose. In patients with advanced NSCLC, the overall response rate (ORR) was 26% in 23 evaluable patients [60]. This is comparable with previous studies, as is the median time to progression of 3.5 months and a median overall survival of 6 months. These studies, in which various single agents such as vinorelbine, gemcitabine, and taxanes were used, revealed response rates ranging from 8% to 50%, and the median overall survival ranged from 6-11 months [61-66].

[00018] In advanced gastric cancer, chemotherapy is provided for palliative purposes. Combination chemotherapy with agents such as 5-FU/doxorubicin combined with mitomycin or methotrexate or the epirubicin/cisplatin/5-FU regimen are frequently used regimens and have shown response rates between 20%-50% [67-70]. Paclitaxel has also shown antitumor activity in patients with advanced gastric cancer (ORR: 5%-23%) in first- and second-line treatment [71-73]. The ORR in this study was 32% in 24 evaluable patients. The toxicity profile of this weekly b.i.d. regimen is well manageable [99]. The most prevalent toxicity in the NSCLC patient group was grade 10 neutropenia, which was observed in 54% of patients. This is comparable with the standard regimen with i.v. paclitaxel every 3 weeks [65, 66].

[00019] The prevalence of neurotoxicity was lower compared with the every 3 weeks regimen, which may be explained by the lower peak plasma concentrations of paclitaxel in this study. This was also observed in patients receiving the 24-hour versus the 3-hour infusion of paclitaxel [74], although it is questionable whether plasma paclitaxel levels after i.v. administration (thus, in the presence of Cremophor EL) can be compared with those after oral paclitaxel (thus, without Cremophor EL).

[00020] For docetaxel, a similar clinical proof-of-concept study was performed in patients with solid tumors. Patients received a course of oral docetaxel at 75 mg/m2 with or without a single oral dose of CsA at 15 mg/kg. Pharmacokinetic results showed that coadministration of oral CsA resulted in a 7.3-fold increase in systemic exposure to docetaxel. The apparent bioavailability of oral docetaxel increased from 8% without CsA to 90% with CsA [75]. This increase in systemic exposure can be explained by CYP3A4 inhibition as well as by P-gp inhibition in the gastrointestinal tract by CsA, but the magnitude of both mechanisms cannot be determined exactly. The effect of CsA on docetaxel bioavailability was less pronounced in mice [49] compared with humans [75], but the reasons for this modest effect in mice were unclear. A phase II study in advanced breast cancer with weekly oral docetaxel plus CsA was also conducted. This regimen was given weekly for 6 weeks, followed by a 2-week break. A weekly oral dose of 100 mg docetaxel was given, leading to an AUC equivalent to a weekly i.v. dose of 40 mg/m2, which was reasonably well tolerated [76]. CsA was given 30 minutes before oral docetaxel intake at a dose of 15 mg/kg. The i.v. docetaxel formulation was used as a drinking solution. In 25 patients evaluable for response, an ORR of 52% was noted. The most frequently observed toxicities were neutropenia, diarrhea, nail toxicity, and fatigue. However, hematologic toxicity appears to be less severe than after i.v. administration [77]. The response rate in this study is in the upper range of results described in the literature [76–79].

[00021] Inter- and intrapatient variabilities in docetaxel AUC after oral administration were in the same range as observed after i.v. docetaxel administration (29%-53%) [80, 81].

[00022] Weekly or b.i.d. administration of an oral dose of CsA in combination with oral docetaxel or paclitaxel could result in renal toxicity or infections due to immunosuppression [82]. Therefore, an alternative drug to improve the clinical bioavailability of oral docetaxel or paclitaxel would, in the view of the present inventors, be preferred.

[00023] Intensive weekly oral regimens with taxanes are feasible and show clinically significant activity in advanced breast cancer, gastric cancer, and NSCLC. The oral regimen is convenient as a favorable hematologic toxicity profile and non-hematologic toxicity is acceptable.

[00024] The prior art appears to be primarily focused on inhibiting P-gp action in order to improve the bioavailability and pharmacokinetic properties of anticancer drugs. This has been done using several drugs, e.g., CsA and GF120918. It appears that P-gp has been observed as the most important protein to block in order to improve the bioavailability of oral drugs.

[00025] Accordingly, in a first aspect, the present invention provides a pharmaceutical composition for oral administration comprising a taxane and a CYP3A4 inhibitor, such as ritonavir, together with one or more pharmaceutically acceptable excipients.

[00026] The advantage of using ritonavir in combination with a taxane is that the oral bioavailability of the taxane is increased, so that more drug is absorbed from the intestine into the bloodstream. This is due to CYP3A4 inhibition, which prevents the drug from being metabolized, and to the reduced Pgp inhibition property. Ritonavir also reduces the elimination of the taxane from the body by inhibiting CYP3A4 metabolism in the liver. This means that a higher blood plasma level of the taxane is achieved over a longer period of time. For example, docetaxel metabolites are less pharmacologically active than docetaxel itself. Therefore, by inhibiting docetaxel metabolism, the more pharmacologically active form is present in the bloodstream at a higher level and for a longer period of time. This provides a greater therapeutic effect. As a result, it may be possible to reduce the amount of taxane per dose. Furthermore, CYP3A4 inhibition reduces interpatient variability in bioavailability and elimination due to different levels of CYP activity in different patients.

[00027] Targeting and inhibiting CYP3A4 with ritonavir rather than targeting P-gp improves the bioavailability of oral taxanes by preventing their metabolism. This, as a whole, is a different approach than that followed by the prior art.

[00028] The pharmaceutical compositions of the present invention comprise any taxane or pharmaceutically acceptable salts and esters thereof and ritonavir (or pharmaceutically acceptable salts and esters thereof) together with any pharmaceutically acceptable vehicle, adjuvant or carrier. Pharmaceutically acceptable vehicles, adjuvants and carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffering substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin. The pharmaceutical compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable vehicles, adjuvants or carriers.

[00029] The pharmaceutical compositions of the present invention may be orally administered in any orally acceptable form including, but not limited to, capsules, tablets, a powder, or coated granules. Suspensions, solutions, and emulsions, preferably in an aqueous vehicle, may also be employed. Tablets may be formulated for immediate release, extended release, repeated release, or sustained release. They may also, or alternatively, be effervescent, bilayer, and/or coated tablets. Extended-release, repeated-release, and sustained-release formulations may be for one or both active ingredients. Tablets may be formed from solid dispersions or solid solutions of the taxane and/or ritonavir. Capsules may be formulated for immediate release, extended release, repeated release, or sustained release. They may be solid-filled or liquid-filled capsules. Extended-release, repeated-release, and sustained-release formulations may be for one or both active ingredients. Capsules can be formed from solid dispersions or solid solutions of the taxane and/or ritonavir, or the taxane and/or ritonavir can be dissolved or dispersed in a liquid. For example, a possible solvent for liquid-filled capsules is triacetin. This appears to be a particularly good solvent for paclitaxel. Aqueous solutions can be "ready-to-use," prepared from powder(s), prepared from a solid dispersion(s), or from mixed solutions of the taxane and ritonavir. Aqueous solutions can also contain other pharmaceutical excipients, e.g., polysorbate 80 and ethanol. For tablets and capsules for oral use, commonly used carriers include sucrose, cyclodextrins, polyethylene glycols, polymethacrylates, polyoxyethylene fatty acid sorbitan esters, polyoxyethylene stearates, mannitol, insulin, sugars (dextrose, galactose, sucrose, fructose, or lactose), HPMC (hydroxypropyl methyl cellulose), PVP (polyvinyl pyrrolidone), and cornstarch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For tablets and capsules, other pharmaceutical excipients that may be added are binders, fillers, fillers/binders, adsorbents, wetting agents, disintegrants, lubricants, glidants, surfactants, and the like. Tablets and capsules may be coated to alter their appearance or properties, for example, to change the taste or color of the tablet or capsule coating. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, and/or coloring agents may be added.

[00030] Solid dispersions or solid solutions of the taxane and ritonavir can be formed using any suitable method and can include carriers, e.g., polymers. Such methods are well known to those skilled in the art [93, 94]. The taxane and ritonavir in the solid dispersion can be in an amorphous, crystalline, or partially amorphous/partially crystalline state. Often, organic solvents are used in the preparation of solid dispersions. These can be any organic solvent, e.g., TBA (tertiary butyl alcohol), ethanol, methanol, DMSO (dimethyl sulfoxide), and IPA (isopropyl alcohol). Any methods for removing organic and/or aqueous solvents from solid dispersion solutions can be used, e.g., lyophilization, spray drying, spray drying-lyophilization, and vacuum drying.

[00031] In compositions, particularly solid compositions, for oral administration, the taxane and ritonavir may be present in the same dosage form or may be present in distinct dosage forms. If present in the same dosage form, the taxane and ritonavir may be formulated together or may be present in distinct compartments of a multi-compartment dosage form, such as a multilayer tablet or a compartmentalized capsule.

[00032] For compositions comprising modified-release formulations, e.g., extended-release, repeated-release, and sustained-release formulations, the aim is to maintain adequate blood levels of one or both active ingredients for an extended period of time after administration.

[00033] A repeat-release formulation, e.g., a tablet or capsule, is one which is capable of releasing an adequate dose of taxane (e.g., docetaxel) and ritonavir immediately (e.g., at time t = 0 h) and releasing an additional booster dose of ritonavir later (e.g., at time t = 4 h, when ritonavir Cmax is typically reached). This can be achieved, for example, by separating the initial doses of docetaxel and ritonavir from the booster dose of ritonavir by an enteric coating or a polymeric coating containing enzymatically cleavable bonds, which allows the coating to be broken down and dissolved in the intestine. Alternatively, this can be achieved by filling a capsule with coated and uncoated pellets, where the coated pellets contain only ritonavir and the uncoated pellets contain docetaxel and ritonavir. This could, of course, also be achieved by combining an immediate-release docetaxel capsule/tablet with a repeated-release ritonavir capsule/tablet. Any suitable enteric coating may be used, e.g., cellulose acetate phthalate, polyvinyl acetate phthalate, and suitable acrylic derivatives, e.g., polymethacrylates.

[00034] In one embodiment, a second booster dose (thus a total of three doses) of ritonavir could be delivered via the same principle, i.e., repeated release, a few hours after the first booster dose (e.g., when the Cmax of the first booster dose of ritonavir is reached).

[00035] A sustained release formulation is one which is capable, for example, of releasing an adequate dose of taxane and an initial priming/loading dose of ritonavir, followed by the slow release of a maintenance dose of ritonavir. For example, this could be achieved by a single oral dose form of docetaxel and ritonavir or by combining an immediate-release docetaxel tablet/capsule with a sustained-release ritonavir tablet/capsule.

[00036] Modified-release formulations may, for example, utilize inert insoluble matrices, hydrophilic matrices, ion-exchange resins, osmotically controlled formulations, and reservoir systems. A typical modified-release system could, for example, consist of the following substances: active drug(s), release-controlling agent(s) (e.g., matrix formers, membrane formers), matrix or membrane modifiers, solubilizer, pH modifier, lubricant and flow aid, supplemental coatings, and density modifiers [84]. Suitable inert excipients include dibasic calcium phosphate, ethyl cellulose, methacrylate copolymer polyamide, polyethylene, polyvinyl acetate. Suitable lipid excipients include carnauba wax, acetyl alcohol, hydrogenated vegetable oils, microcrystalline waxes, mono- and triglycerides, PEG monostearate, and PEG. Suitable hydrophilic excipients include alginates, carbopol, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and methyl cellulose [84].

[00037] In one embodiment of the invention, the composition comprising a taxane and ritonavir may be formulated such that the ritonavir is released slightly earlier or faster than the taxane. This will have the effect of inhibiting CYP3A4 enzymes in the intestine before a substantial amount of the taxane has been released from the composition. Therefore, this will reduce the amount of the taxane that is broken down by CYP3A4 enzymes before it reaches the bloodstream and, due to the effect of ritonavir on CYP3A4 in the liver, will also have the effect of reducing the metabolism and elimination of the taxane that reaches the bloodstream during the early stages of its absorption. This effect is demonstrated by Figure 1, which shows a trend that administering ritonavir 60 mins before docetaxel increases oral bioavailability and AUC. Although this result is not statistically significant in Example 2, this trend can be observed.

[00038] Taxanes are diterpene compounds that originate from plants of the genus Taxus (yews). However, some taxanes have now been produced synthetically. Taxanes inhibit cell growth by stopping cell division and are used in the treatment of cancer. They stop cell division by disrupting microtubule formation. They can also act as angiogenesis inhibitors. The term "taxane" as used herein includes all diterpene taxanes, whether naturally or artificially produced, functional derivatives, and pharmaceutically acceptable salts or esters which bind to tubulin and/or are substrates for CYP3A4. Preferred taxanes are docetaxel, paclitaxel, BMS-275183, functional derivatives thereof, and pharmaceutically acceptable salts or esters thereof. BMS-275183 is a C-3'-t-butyl-3'-N-t-butyloxycarbonyl analogue of paclitaxel [83]. The most preferred taxane is docetaxel, a functional derivative thereof, or a pharmaceutically acceptable salt or ester thereof, in particular those derivatives which are substrates for CYP3A4.

[00039] Taxane derivatives containing groups to modify physicochemical properties are also included within the present invention. Thus, polyalkylene glycol (such as polyethylene glycol) or saccharide conjugates of taxanes, with improved or modified solubility characteristics, are included.

[00040] The pharmaceutical composition of the present invention may comprise any suitable amount of the taxane and ritonavir. Preferably, the composition comprises between about 0.1 mg and about 1000 mg of the taxane. Preferably, the composition also comprises between about 0.1 mg and about 1200 mg of ritonavir. The amounts of each of the taxane and ritonavir will depend on the intended frequency of administration of the composition. For example, the composition may be for administration on a three times a day, twice a day, or daily basis, every other day, weekly, every two weeks, every three weeks, or any appropriate dosing interval. Combinations of these dosing regimens may also be used, for example, the composition may be for an amino acid twice a day, once a week, or every two or three weeks. For example, docetaxel or paclitaxel may be administered on a twice a day basis once a week. The typical weekly dose is divided, so that an individual takes, for example, half the dose in the morning and the other half in the evening once a week. This has the effect of decreasing peak plasma drug levels, which helps reduce side effects. It also increases the overall systemic exposure time of the drug.

[00041] If the composition is for daily administration, the composition preferably comprises between about 0.1 mg and about 100 mg of the taxane, more preferably between about 5 mg and about 40 mg of the taxane, more preferably between about 5 mg and about 30 mg of the taxane, more preferably between about 10 mg and about 20 mg of the taxane, and even more preferably about 15 mg of the taxane. Preferably, the composition also comprises between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, more preferably between about 50 mg and about 200 mg of ritonavir, and even more preferably about 100 mg of ritonavir.

[00042] If the composition is for weekly administration, the composition preferably comprises between about 30 mg and about 500 mg of the taxane, more preferably between about 50 mg and about 200 mg of the taxane, and even more preferably about 100 mg of the taxane. Preferably, the composition also comprises between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, more preferably between about 50 mg and about 200 mg of ritonavir, and even more preferably about 100 mg of ritonavir.

[00043] Surprisingly, it has been found that using ritonavir at a low dose, e.g., 100 mg, still achieves the desired properties of enhancing taxane bioavailability to provide an enhanced therapeutic effect. This means that a lower dose of ritonavir can be used to achieve the desired effect while minimizing the risk of side effects.

[00044] The present invention also provides a composition comprising a taxane and a CYP3A4 inhibitor, such as ritonavir, for use in therapy.

[00045] Furthermore, the present invention also provides a composition comprising a taxane and a CYP3A4 inhibitor, such as ritonavir, for use in the treatment of neoplastic disease.

[00046] The neoplastic disease treated by the present invention is preferably a solid tumor. The solid tumor is preferably selected from breast, lung, gastric, colorectal, head and neck, esophageal, liver, renal, pancreatic, bladder, prostate, testicular, cervical, endometrial, ovarian, and non-Hodgkin's lymphoma (NHL) cancers. The solid tumor is more preferably selected from breast, gastric, ovarian, prostate, head and neck, and non-small cell lung cancers.

[00047] In one embodiment, treating the neoplastic disease comprises administering the composition and subsequently, after a predetermined period of time, administering a booster dose of ritonavir. The booster dose is preferably administered between about 0 hours and about 12 hours after compounding, more preferably between about 1 hour and about 10 hours after compounding, more preferably between about 2 hours and about 8 hours after compounding, more preferably between about 3 hours and about 5 hours after compounding, and even more preferably about 4 hours after compounding. The booster dose is preferably between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, most preferably between about 50 mg and about 200 mg of ritonavir, and even more preferably about 100 mg of ritonavir.

[00048] Surprisingly, it has been found that administering a booster dose of ritonavir provides a therapeutic level of the taxane in the bloodstream for a longer period of time, thereby having a greater therapeutic effect.

[00049] In a related aspect, the present invention also provides a method of treating a neoplastic disease comprising administering to a subject in need of such treatment an effective amount of a taxane and a CYP3A4 inhibitor, such as ritonavir.

[00050] As per the above composition, the taxane may be any suitable taxane. Preferably, the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof, and pharmaceutically acceptable salts or esters thereof, and more preferably, the taxane is docetaxel, a functional derivative thereof, or a pharmaceutically acceptable salt or ester thereof.

[00051] When the taxane and ritonavir are being administered to the subject, they may be administered substantially simultaneously with each other. Alternatively, they may be administered separately from each other. When they are administered separately, ritonavir is preferably administered before the taxane, and more preferably approximately 60 minutes before the taxane.

[00052] "Substantially simultaneously" as used herein means administration of the taxane or ritonavir within approximately 20 minutes, more preferably within 15 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, most preferably within 2 minutes of the ritonavir or taxane. Generally, the ritonavir should be administered simultaneously with or before the taxane. The ritonavir and taxane may, in some embodiments, be administered simultaneously, i.e., together in one formulation or simultaneously in separate formulations.

Any suitable amount of the taxane and ritonavir may be administered according to the method. The dose of taxane and/or ritonavir may be administered in a flat dose (i.e., the same for all patients regardless of weight or body surface area) or a weight-based dose or a body surface area-based dose. Preferably, the taxane and/or ritonavir is administered in a flat dose. Preferably, between about 0.1 mg and about 1000 mg of the taxane is administered. Preferably, between about 0.1 mg and about 1200 mg of ritonavir is administered. The amounts of each of the taxane and ritonavir administered will depend on the intended frequency of administration of the taxane and ritonavir. For example, administration may be on a three times a day basis or daily, every other day, weekly, every two weeks, every three weeks, or any other suitable dosing interval. Combinations of these dosing regimens may also be used, for example, twice-daily, once-weekly, or every two to three weeks.

[00054] If the method involves daily administration of the taxane and ritonavir, preferably between about 0.1 mg and about 100 mg of the taxane is administered, more preferably between about 5 mg and about 40 mg of the taxane is administered, more preferably between about 5 mg and about 30 mg of the taxane is administered, more preferably between about 10 mg and about 20 mg of the taxane is administered, and even more preferably about 15 mg of the taxane. Preferably, between about 50 mg and about 1200 mg of ritonavir is also administered, more preferably between about 50 mg and about 500 mg of ritonavir is administered, more preferably between about 50 mg and about 200 mg of ritonavir is administered, and most preferably about 100 mg of ritonavir is administered.

[00055] If the method involves weekly administration of the taxane and ritonavir, preferably between about 30 mg and about 500 mg of the taxane is administered, more preferably between about 50 mg and about 200 mg of the taxane is administered, and most preferably about 100 mg of the taxane is administered. Preferably, between about 50 mg and about 1200 mg of ritonavir is also administered, more preferably between about 50 mg and about 500 mg of ritonavir is administered, more preferably between about 50 mg and about 200 mg of ritonavir is administered, and most preferably about 100 mg of ritonavir is administered.

[00056] The method may be for the treatment of any neoplastic disease. Preferably, the neoplastic disease is a solid tumor. Preferably, the solid tumor is selected from breast, lung, gastric, colorectal, head and neck, esophageal, liver, renal, pancreatic, bladder, prostate, testicular, cervical, endometrial, ovarian, and NHL cancers. More preferably, the solid tumor is selected from breast, ovarian, prostate, gastric, head and neck, and non-small cell lung cancers.

[00057] Preferably, the method is used to treat a human being.

[00058] In one embodiment, the method further comprises administering a booster dose of a CYP3A4 inhibitor, such as ritonavir, a certain period of time after administration of the first dose of ritonavir (i.e., the dose of ritonavir combined with the dose of the taxane). The booster dose is preferably administered between about 0 hours and about 12 hours after compounding, more preferably between about 1 hour and about 10 hours after compounding, more preferably between about 2 hours and about 8 hours after compounding, more preferably between about 3 hours and about 5 hours after compounding, and most preferably about 4 hours after compounding. The booster dose is preferably between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, most preferably between about 50 mg and about 200 mg of ritonavir, and even more preferably about 100 mg of ritonavir.

[00059] The present invention also provides a method of treating a neoplastic disease, the method comprising administering a composition comprising a taxane and one or more pharmaceutically acceptable excipients, to a subject who is receiving a CYP3A4 inhibitor, such as ritonavir, simultaneously, separately or sequentially with the taxane.

[00060] The present invention further provides a method of treating a neoplastic disease, the method comprising administering a composition comprising a CYP3A4 inhibitor, such as ritonavir, and one or more pharmaceutically acceptable excipients, to a subject who is receiving a taxane simultaneously, separately, or sequentially with the CYP3A4 inhibitor, such as ritonavir.

[00061] Additionally, the present invention provides a kit comprising a first pharmaceutical composition comprising a taxane and a second pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, the first and second compositions being suitable for simultaneous, separate or sequential administration for the treatment of neoplastic disease.

[00062] In one embodiment, the kit may further comprise a third pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, suitable for administration subsequent to the second pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir. It will be appreciated that the second and third pharmaceutical compositions in the kit, each comprising a CYP3A4 inhibitor, such as ritonavir, may be unit dose forms of substantially the same composition.

[00063] Alternatively, the kit may comprise a first pharmaceutical composition comprising a taxane and a CYP3A4 inhibitor, such as ritonavir, for the treatment of neoplastic disease. In that case, the kit may further comprise a second pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, suitable for administration subsequent to the first pharmaceutical composition.

[00064] Further, the present invention provides a composition comprising a taxane and one or more pharmaceutically acceptable excipients for use in the treatment of neoplastic disease in a subject who is receiving a CYP3A4 inhibitor, such as ritonavir, simultaneously, separately or sequentially with the taxane.

[00065] Further, the present invention provides a composition comprising a CYP3A4 inhibitor, such as ritonavir, and one or more pharmaceutically acceptable excipients, for use in the treatment of neoplastic disease in a subject who is receiving a taxane simultaneously, separately, or sequentially with the CYP3A4 inhibitor, such as ritonavir.

[00066] It will be appreciated by those skilled in the art that any or all of the preferred features described above with respect to compositions, methods or kits employing ritonavir are equally applicable to those employing other CYP3A4 inhibitors, for example, grapefruit juice or St. John's wort (or components of both), lopinavir or imidazole compounds such as ketoconazole.

[00067] Another problem associated with the prior art is that it has not been possible to develop an oral composition comprising a taxane in which the taxane has high bioavailability with low variability. Clinical studies with oral paclitaxel [e.g., 3] and oral docetaxel [e.g., 75] have been performed where i.v. taxane formulations (also containing excipients such as Cremophor EL and ethanol or polysorbate 80 and ethanol) were ingested orally. Nausea, vomiting, and an unpleasant taste are frequently reported by patients.

[00068] As discussed previously, Chen et al. [95] attempted to use a solid dispersion of docetaxel in combination with poloxamer 188 or PVP-K30 to improve the solubility and dissolution rate of docetaxel. Poloxamer increased the solubility of docetaxel to about 3.3 Qg/ml after 20 minutes and to a maximum of about 5.5 Dg/ml after about 120 minutes when a docetaxel to poloxamer ratio of 5:95 was used (see Figure 7 in Chen's paper). PVP-K30 increased the solubility of docetaxel to about 0.8 Qg/ml after 20 minutes and to a maximum of about 4.2 Qg/ml after about 300 minutes (see Figure 2). In order to obtain good oral bioavailability, a drug must have a relatively high solubility and dissolution rate, so that there is a high enough amount of the drug in solution within the first approximately 0.5 to 1.5 hours.

[00069] In another aspect, the present invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic and preferably polymeric carrier, and a surfactant.

[00070] The advantage provided by the composition of this aspect is that the solubility of the taxane is increased to a surprising degree. Furthermore, the dissolution rate of the taxane is also increased to a surprising degree. Both of these factors result in a significant increase in the bioavailability of the taxane. This is believed to be due, at least in part, to the taxane being in an amorphous state. Crystalline taxanes have very low solubilities. Furthermore, in clinical trials, the oral compositions of the invention were found to provide a high AUC and an inter-subject variability that was significantly lower than the inter-subject variability demonstrated by a liquid formulation. This provides a much more predictable exposure to the taxane, which is very desirable from a safety perspective in oral chemotherapy regimens. The inter-subject variability also appears to be significantly lower. Another advantage is that the oral composition of the invention appears to be at least equally or better tolerated (i.e., in terms of side effects). Good physical stability ensures that taxane solubility remains high.

[00071] The surfactant also helps maintain the taxane in an amorphous state when placed in aqueous media and, surprisingly, substantially increases the solubility of the taxane compared to compositions comprising an amorphous taxane and a vehicle.

[00072] The term "substantially amorphous" means that there will be little or no long-range order in the position of the taxane molecules. Most of the molecules should be randomly oriented. A completely amorphous structure has no long-range order and contains no crystalline structure; it is the opposite of a crystalline solid. However, a completely amorphous structure can be difficult to obtain for some solids. Therefore, many "amorphous" structures are not completely amorphous, but still contain some amount of crystallinity or long-range order. For example, a solid may be mostly amorphous but have pockets of crystalline structure, or it may contain very small crystals, such that it borders on being truly amorphous. Therefore, the term "substantially amorphous" encompasses solids that have some amorphous structure, but which also have some crystalline structure as well. The crystallinity of a substantially amorphous taxane should be less than 50%. Preferably, the crystallinity of the substantially amorphous taxane is less than 40%, even more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably less than 15%, even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5%, and most preferably less than 2.5%. Since crystalline taxanes have low solubility, the lower the crystallinity of the substantially amorphous taxane, the better the solubility of the substantially amorphous taxane.

[00073] The substantially amorphous taxane may be prepared in any suitable manner, and methods will be apparent to those skilled in the art. For example, it may be prepared using a solvent evaporation or lyophilization method. Preferably, the amorphous taxane is prepared by lyophilization. Surprisingly, it has been found that preparing the amorphous taxane using lyophilization results in a composition having improved solubility and dissolution rate compared to an evaporation method. This is believed to be because the lyophilization method produces a more amorphous taxane compared to the solvent evaporation method.

[00074] The composition for oral administration is in a solid form. The solid composition may be in any suitable form, provided that the taxane is in a substantially amorphous state. For example, the composition may comprise a physical mixture of the amorphous taxane, carrier, and surfactant. Preferably, the taxane and carrier are in the form of a solid dispersion. The term "solid dispersion" is well known to those skilled in the art and means that the taxane is partially molecularly dispersed in the carrier. More preferably, the carrier and taxane are in the form of a solid solution. The term "solid solution" is well known to those skilled in the art and means that the taxane is substantially completely molecularly dispersed in the carrier. It is believed that solid solutions are more amorphous in nature than solid dispersions. Methods of preparing solid dispersions and solid solutions are well known to those skilled in the art [93, 94]. Using these methods, the taxane and carrier are in an amorphous state. When the taxane and vehicle are in a solid dispersion or solution, the solubility and dissolution rate of the taxane are greater than that of a physical mixture of amorphous taxane and vehicle. It is believed that when the taxane is in a solid dispersion or solution, the taxane is in a more amorphous state compared to the amorphous taxane itself. This is believed to result in improved solubility and dissolution. The crystallinity of the solid dispersion or solution should be less than 50%. Preferably, the crystallinity of the solid dispersion or solution is less than 40%, even more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably less than 15%, even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5%, and most preferably less than 2.5%.

[00075] When the taxane and carrier are in a solid dispersion, the surfactant may be in a physical mixture with the solid dispersion or solution. Preferably, however, the composition comprises a taxane, carrier, and surfactant in the form of a solid dispersion or, more preferably, a solid solution. The advantage of having all three components in a solid dispersion or solution is that it allows the use of a smaller amount of surfactant to achieve the same improvement in solubility and dissolution rate.

[00076] In one embodiment, the composition may be contained in a capsule for oral administration. The capsule may be filled in a variety of ways. For example, the amorphous taxane may be prepared by lyophilization, powder formation, mixing with the carrier and surfactant, and then dispensing into the capsule. In an alternative preferred embodiment, the amorphous taxane is prepared by lyophilizing a taxane solution into a capsule for oral administration. The taxane solution containing the required amount of taxane is dispensed into the capsule and then lyophilized while still contained within the capsule. This makes it easier to dispense the required amount of taxane into the capsule, since it is easier to dispense liquids rather than powders. It also eliminates the capsule filling step, making the process more efficient. Carrier and powdered surfactant may then be added. Preferably, the capsule is an HPMC capsule.

[00077] If the taxane and vehicle are in the form of a solid dispersion or solution, the solution containing the taxane and vehicle is preferably dispensed into the capsule and then lyophilized while still in the capsule. Thus, the solid dispersion or solution is prepared by lyophilizing a solution of taxane and vehicle into a capsule for oral administration. This again eliminates the capsule filling step. Powdered surfactant can then be added.

[00078] If the taxane, vehicle, and surfactant are in the form of a solid dispersion or solution, the solution containing the taxane, vehicle, and surfactant is preferably dispensed into the capsule and then lyophilized while still in the capsule. In this way, the solid dispersion or solution is prepared by lyophilizing a solution of taxane, vehicle, and surfactant into a capsule for oral administration. This, again, eliminates the capsule filling step and eliminates the need to handle powders, which can be problematic.

[00079] The taxane of the composition may be any suitable taxane as defined above. Preferably, the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof, and pharmaceutically acceptable salts or esters thereof. More preferably, the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof, and pharmaceutically acceptable salts or esters thereof.

[00080] The hydrophilic, and preferably polymeric, carrier of the composition is an organic, and preferably polymeric, compound capable of at least partial dissolution in aqueous media at a pH of 7.4 and/or capable of swelling or gelling in such aqueous media. The carrier may be any hydrophilic, and preferably polymeric, carrier which ensures that the taxane remains in an amorphous state in the composition and increases the solubility and dissolution rate of the taxane. Preferably, the carrier is selected from: polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); crospovidone (PVP-CL); polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-PVA); cellulose derivatives, such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), cellulose acetate phthalate, and hydroxypropyl methyl cellulose phthalate; polyacrylates; polymethacrylates; sugars, polyols, and their polymers, such as mannitol, sucrose, sorbitol, dextrose, and chitosan; and cyclodextrins. More preferably, the carrier is selected from PVP, PEG, and HPMC, and even more preferably, the carrier is PVP.

[00081] If the vehicle is PVP, it can be any suitable PVP [98] to act as a vehicle and help maintain the taxane in an amorphous state. For example, a PVP can be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90, and PVP-K120. Preferably, the PVP is selected from PVP-K30, PVP-K60, and PVP-K90.

[00082] The composition may contain any suitable amount of the carrier relative to the amorphous taxane, such that the carrier maintains the amorphous taxane in its amorphous state. Preferably, the weight ratio of taxane to carrier is between about 0.01:99.99 w/w and about 75:25 w/w. More preferably, the weight ratio of taxane to carrier is between about 0.01 : 99.99 w/w and about 50 : 50 w/w, still more preferably, between about 0.01 : 99.99 w/w and about 40 : 60 w/w, still more preferably, between about 0.01 : 99.99 w/w and about 30 : 70 w/w, still more preferably, between about 0.1 : 99.9 w/w and about 20 : 80 w/w, still more preferably, between about 1 : 99 w/w and about 20 : 80 w/w, still more preferably, between about 2.5 : 97.5 w/w and about 20 : 80 w/w, still more preferably, between about 2.5:97.5 weight/weight and about 15:85 weight/weight, even more preferably between about 5:95 weight/weight and about 15:85 weight/weight, and most preferably about 10:90 weight/weight.

[00083] The surfactant may be any pharmaceutically acceptable surfactant and such surfactants are well known to those skilled in the art. Preferably, the surfactant is selected from triethanolamine, sunflower oil, stearic acid, monobasic sodium phosphate, sodium citrate dihydrate, propylene glycol alginate, oleic acid, monoethanolamine, mineral oil and lanolin alcohols, methyl cellulose, medium chain triglycerides, hydrated lanolin, lanolin, hydroxypropyl cellulose, glyceryl monostearate, ethylene glycol palmitostearate, diethanolamine, lanolin alcohols, cholesterol, cetyl alcohol, cetostearyl alcohol, castor oil, sodium dodecyl sulfate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives of castor oil, polyoxyethylene alkyl ethers, poloxamer, Glyceryl monooleate, sodium docusate, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax, and triethyl citrate. More preferably, the surfactant is selected from sodium dodecyl sulfate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, poloxamer, glyceryl monooleate, sodium docusate, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax, and triethyl citrate. Most preferably, the surfactant is SDS.

[00084] Any suitable amount of surfactant may be used in the composition to improve the solubility and dissolution rate of the taxane. Preferably, the weight ratio of surfactant to taxane and vehicle combined is between about 1:99 weight/weight and about 50:50 weight/weight, more preferably between about 1:99 weight/weight and about 44:56 weight/weight, still more preferably between about 1:99 weight/weight and about 33:67 weight/weight, still more preferably between about 2:98 weight/weight and about 33:67 weight/weight, still more preferably between about 2:98 weight/weight and about 17:83 weight/weight, still more preferably between about 5:95 weight/weight and about 17:83 weight/weight, and most preferably about 9:91 weight/weight.

Alternatively, the weight ratio of surfactant to taxane is preferably between about 1:100 weight/weight and about 60:1 weight/weight, more preferably between about 1:50 weight/weight and about 40:1 weight/weight, still more preferably between about 1:20 weight/weight and about 20:1 weight/weight, still more preferably between about 1:10 weight/weight and about 10:1 weight/weight, still more preferably between about 1:5 weight/weight and about 5:1 weight/weight, still more preferably between about 1:3 weight/weight and about 3:1 weight/weight, still more preferably between about 1:2 weight/weight and about 2:1 weight/weight, and still more preferably between about 1:3 weight/weight and about 3:1 weight/weight, still more preferably between about 1:2 weight/weight and about 2:1 weight/weight, and still more preferably between about 1:3 weight/weight and about 3:1 weight/weight, still more preferably between about 1:3 weight/weight and about 3:1 weight/weight, and still more preferably between about 1:3 weight/weight and about 3:1 weight/weight. preferably about 1:1 weight/weight.

[00086] The unit dose of the taxane contained in the composition will depend on the intended frequency of administration of the composition. Suitable dosages and frequency of administration are discussed above with respect to the taxane and ritonavir composition.

[00087] In one embodiment, the composition comprises an enteric coating. Suitable enteric coatings are described above. An enteric coating prevents release of the taxane in the stomach and thereby prevents acid-mediated degradation of the taxane. Furthermore, it allows for targeted delivery of the taxane to the intestine where the taxane is absorbed, thereby ensuring that the limited time during which the taxane is present in solution (before crystallization occurs) is consumed only at sites where absorption is possible.

[00088] In one embodiment, the composition may further comprise one or more additional pharmaceutically active ingredients. Preferably, one or more of the additional pharmaceutically active ingredients is a CYP3A4 inhibitor. Suitable CYP3A4 inhibitors are discussed above. Preferably, the CYP3A4 inhibitor is ritonavir.

[00089] The pharmaceutical composition may comprise additional pharmaceutically acceptable adjuvants and carriers which are well known to those skilled in the art. Pharmaceutically acceptable adjuvants and carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, whey proteins such as human serum albumin, buffering substances such as phosphates, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, and lanolin.

[00090] The pharmaceutical compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, a coated powder or granules. Tablets may be formulated for immediate release, extended release, repeated release, or sustained release. They may also, or alternatively, be effervescent, bilayer, and/or coated tablets. Capsules may be formulated to be immediate, extended release, repeated release, or sustained release. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For tablets and capsules, other pharmaceutical excipients that may be added are binders, fillers, fillers/binders, adsorbents, wetting agents, disintegrants, lubricants, glidants, and the like. Tablets and capsules may be coated to change the appearance or properties of the tablets and capsules, for example, to change the taste or color of the tablet or capsule coating.

[00091] Other pharmaceutically acceptable additives which may be added to the composition are well known to those skilled in the art, some of which are discussed above with respect to the composition according to the first aspect of the invention.

[00092] The present invention also provides the above composition for use in therapy.

[00093] Further, the present invention provides the above composition for use in the treatment of neoplastic disease. Suitable neoplastic diseases are discussed above.

[00094] The present invention also provides a method of treating a neoplastic disease, the method comprising administering to a subject in need of such treatment an effective amount of the above composition.

[00095] Preferably, the method is used to treat a human being.

[00096] It will be appreciated by those skilled in the art that the composition of the invention comprising a substantially amorphous taxane and carrier can be used in the methods described above with respect to the use of a taxane or a CYP3A4 inhibitor or ritonavir, where appropriate.

[00097] In another aspect, the present invention provides a pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by lyophilization.

[00098] The advantage provided by this composition is that it provides increased solubility of the taxane and also an increased dissolution rate. This is believed to be because the freeze-drying method produces a more amorphous taxane compared to other methods of producing amorphous taxanes. It is believed that the more amorphous nature of the taxane provides the increased solubility and dissolution rate.

[00099] Additional optional features of the composition are the same as for the composition comprising an amorphous taxane, a carrier, and a surfactant. For example, the composition comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by lyophilization, preferably further comprises a surfactant. Preferred embodiments of the taxane, the carrier, the crystallinity of the taxane, the ratio of taxane to carrier, the state of the taxane and carrier, etc. are the same as defined above.

BRIEF DESCRIPTION OF THE FIGURES

[000100] The present invention will now be described, by way of example only, with reference to the attached figures, in which:

[000101] Figure 1 is a graph showing docetaxel plasma concentration over time comparing oral administration with ritonavir (RTV) (simultaneous and with ritonavir given 60 mins before docetaxel) with i.v. administration (without ritonavir); oral docetaxel dose: 100 mg. The commercially available i.v. docetaxel formulation (Taxotere®; 2 ml = 80 mg docetaxel; excipient polysorbate 80) was diluted with 95% ethanol: water (13:87) to provide a 10 mg/ml docetaxel solution, which patients drank (10 ml of the 10 mg/ml solution) with 100 ml of tap water. Ritonavir dose: 1 capsule with 100 mg ritonavir (Norvir®);

[000102] Figure 2 is a graph showing plasma ritonavir concentration against time comparing oral administration of ritonavir (100 mg dose; Norvir®, capsule) concurrently with oral docetaxel or 60 mins before oral docetaxel. T = 0 is when docetaxel is administered. Therefore, the first part of the curve corresponding to ritonavir administered before docetaxel is not visible. Oral docetaxel dose: 100 mg. The commercially available i.v. docetaxel formulation (Taxotere®; 2 ml = 80 mg docetaxel; excipient polysorbate 80) was diluted with 95:water (13:87) ethanol to provide a 10 mg/ml docetaxel solution, which patients drank (10 ml of the 10 mg/ml solution) with 100 ml of tap water. Ritonavir dose: 1 capsule with 100 mg of ritonavir (Norvir®);

[000103] Figure 3 is a pharmacokinetic model of oral docetaxel in combination with ritonavir (RTV). The different compartments in the pharmacokinetic model are as follows:

[000104] C1 - gastrointestinal tract (oral docetaxel entry compartment)

[000105] C2 - central compartment (docetaxel)

[000106] C3 - first peripheral compartment (docetaxel)

[000107] C4 - second peripheral compartment (docetaxel)

[000108] C5 - gastrointestinal tract (ritonavir entry compartment)

[000109] C6 - central compartment (ritonavir)

[000110] C7 - active CYP3A4 enzyme;

[000111] C8 - inactive CYP3A4 enzyme;

[000112] C2 - central compartment (docetaxel)C3 - first peripheral compartment (docetaxel)C4 - second peripheral compartment (docetaxel)C5 - gastrointestinal tract (entry compartment of)C6 - central compartment (ritonavir)C7 - active CYP3A4 enzyme;C8 - inactive CYP3A4 enzyme;Figure 4 is a graph showing, for a series of subjects, each row representing one subject, the relative amount of CYP3A4 enzyme against time for oral docetaxel in combination with ritonavir;

[000113] Figure 5 shows the results of a dissolution test of solid paclitaxel dispersions versus physical mixtures of paclitaxel (conditions: 900 mL WfI, 37°C, 75 rpm);

[000114] Figure 6 shows the results of a dissolution test of paclitaxel solid dispersion (PCT) capsules with and without sodium dodecyl sulfate (conditions: 900 mL WfI, 37°C, 75 rpm);

[000115] Figure 7 shows the results of a dissolution test of solid dispersions of paclitaxel with sodium dodecyl sulfate incorporated into the solid dispersion or added to the capsule (conditions: 500 mL WfI, 37°C, 75 rpm (100 rpm for SDS added to the capsules));

[000116] Figure 8 shows the results of a dissolution test of solid dispersions of paclitaxel with various vehicles (conditions: 500 mL WfI, 37°C, 100 rpm);

[000117] Figure 9 shows the results of a solubility test of paclitaxel/PVP-K17 solid dispersions with various drug-carrier ratios (conditions: 25 mL WfI, 37°C, 7200 rpm);

[000118] Figure 10 shows the results of a dissolution test of solid dispersions of paclitaxel in various media (conditions: 500 mL FaSSIF (light gray), 37°C, 75 rpm; or 500 mL SGFsp and 629 mL SIFsp, 37°C, 75 rpm (dark gray));

[000119] Figure 11 shows the solubility of docetaxel from five different formulations (see Table 15). A: anhydrous docetaxel; B: amorphous docetaxel; C: physical mixture of anhydrous docetaxel, PVP-K30, and SDS; D: physical mixture of amorphous docetaxel, PVP-K30, and SDS; E: solid dispersion of amorphous docetaxel, PVP-K30, and SDS (dissolution conditions: ± 6 mg docetaxel, 25 mL WfI, 37 °C, 720 rpm);

[000120] Figure 12 shows the solubility of docetaxel solid dispersions with different vehicles (see Table 15). E: Solid dispersion of amorphous docetaxel, PVP-K30, and SDS; F: Solid dispersion of amorphous docetaxel, HPβ-CD, and SDS. (Dissolution conditions: ± 6 mg Docetaxel, 25 mL WfI, 37 °C, 720 rpm);

[000121] Figure 13 shows the solubility of solid dispersions of docetaxel with PVP of various chain lengths (see Table 15). E: solid dispersion of amorphous docetaxel, PVP-K30, and SDS; G: solid dispersion of amorphous docetaxel, PVP-K12, and SDS; H: solid dispersion of amorphous docetaxel, PVP-K17, and SDS; I: solid dispersion of amorphous docetaxel, PVP-K25, and SDS; J: solid dispersion of amorphous docetaxel, PVP-K90, and SDS. (Dissolution conditions: ± 6 mg Docetaxel, 25 mL WfI, 37 °C, 720 rpm);

[000122] Figure 14 shows the solubility of docetaxel solid dispersions with various drug loadings (see Table 15). E: 1/11 docetaxel; K: 5/7 docetaxel; L: 1/3 docetaxel; M: 1/6 docetaxel; N: 1/21 docetaxel. (Dissolution conditions: ± 6 mg Docetaxel, 25 mL WfI, 37 °C, 720 rpm);

[000123] Figure 15 shows the dissolution results in terms of the relative amount of docetaxel dissolved from a solid dispersion of docetaxel, PVP-K30, and SDS, compared with literature data from a solid dispersion of docetaxel and PVP-K30 [Chen et al., 95];

[000124] Figure 16 shows the dissolution results in terms of the absolute amount of docetaxel dissolved from a solid dispersion of docetaxel, PVP-K30 and SDS, compared with literature data from a solid dispersion of docetaxel and PVP-K30 [Chen et al., 95];

[000125] Figure 17 shows the results of a dissolution test of docetaxel capsules (15 mg docetaxel (DXT) per capsule with PVP-K30 + SDS) compared with literature data (Chen et al.) [95];

[000126] Figure 18 shows the dissolution results in terms of the absolute amount of docetaxel dissolved from a solid dispersion of docetaxel, PVP-K30 and SDS. The dissolution test was performed in Simulated Intestinal Fluid sine Pancreatin (SIFsp);

[000127] Figure 19 shows the dissolution results in terms of the relative amount of docetaxel dissolved from a solid dispersion of docetaxel, PVP-K30 and SDS. The dissolution test was performed in Simulated Intestinal Fluid sine Pancreatin (SIFsp);

[000128] Figure 20 shows the pharmacokinetic curves of a patient who received docetaxel and ritonavir simultaneously in a first cycle. In the second cycle, the patient received docetaxel and ritonavir simultaneously at t = 0 and then an additional booster dose of ritonavir at t = 4 h;

[000129] Figure 21 shows the pharmacokinetic curves of patients receiving the liquid oral formulation of docetaxel compared with patients receiving the solid oral formulation of docetaxel (MODRA); and

[000130] Figure 22 shows the pharmacokinetic curves of four patients who received a liquid formulation of docetaxel and/or a solid dispersion comprising docetaxel (referred to as MODRA);

[000131] Figure 23 shows the pharmacokinetic curves after i.v. and oral administration of docetaxel. I.v. and oral administration was combined with ritonavir administration. N.B. The calculated bioavailability is corrected for the administered dose.

Example 1

[000132] A 100 mg dose of ritonavir was combined with a 100 mg dose of docetaxel and orally administered simultaneously to 22 patients. A comparison was made with i.v. docetaxel (100 mg) (Taxotere®) given as a 1-hour i.v. infusion (standard procedure) (without ritonavir).

[000133] Oral ritonavir: 1 capsule with 100 mg of ritonavir (Norvir®). Oral docetaxel dose: 100 mg. The commercially available i.v. docetaxel formulation (Taxotere®; 2 ml = 80 mg of docetaxel; excipient polysorbate 80) was diluted with 95% ethanol: water (13:87) to provide a 10 mg/ml docetaxel solution, which patients drank (10 ml of the 10 mg/ml solution) with 100 ml of tap water.

[000134] The pharmacokinetic data that were obtained are as follows:

[000135] Oral docetaxel AUC without ritonavir 0.29 ± 0.26 (mg.h/L)

[000136] Oral docetaxel AUC with ritonavir 2.4 ± 1.5 (mg.h/L)

[000137] Intravenous docetaxel AUC without ritonavir 1.9 ± 0.4 (mg.h/L)

[000138] The results show a dual effect of ritonavir on the absorption and elimination of docetaxel. The AUC of docetaxel increases 8.2-fold when given orally in combination with ritonavir. Surprisingly, the exposure is even higher than that achieved after administration, reflecting the additional effect of ritonavir on the inhibition of docetaxel elimination.

Conclusions

[000139] It has been clearly proven the concept that, in patients, ritonavir can increase the systemic exposure of oral docetaxel to levels that are comparable to or even greater than the levels after intravenous administration of docetaxel at the same dose level. The combination appears to be safe, with very favorable pharmacokinetic characteristics.

Example 2

[000140] Treatment of solid malignancies with oral combination of docetaxel and ritonavir.

[000141] Patients were randomly assigned to two treatment groups, X and Y. Group X received, in the first week, 100 mg of ritonavir followed 60 minutes later by 100 mg of oral docetaxel, and in the second week, these patients received 100 mg of ritonavir and 100 mg of oral docetaxel simultaneously. Patients in group Y received, in the first week, 100 mg of ritonavir and 100 mg of oral docetaxel simultaneously, and in the second week, 100 mg of ritonavir followed 60 minutes later by 100 mg of oral docetaxel. Both groups X and Y received 100 mg of i.v. docetaxel (Taxotere®; standard procedure; as a 1-hour infusion) without ritonavir 15 days after the start of oral administration.

[000142] Oral docetaxel dose: 100 mg. The commercially available i.v. docetaxel formulation (Taxotere®; 2 ml = 80 mg docetaxel; excipient polysorbate 80) was diluted with 95% ethanol: water (13:87) to provide a 10 mg/ml docetaxel solution, which patients drank (10 ml of the 10 mg/ml solution) with 100 ml of tap water. Ritonavir dose: 1 capsule with 100 mg ritonavir (Norvir®).

[000143] Pharmacokinetic results are provided below: Table 1A - DOCETAXEL

Conclusions

[000144] There is no significant difference between co-administration of docetaxel and ritonavir compared with ritonavir administered 60 minutes before docetaxel. The AUC for oral administration is higher than the AUC for intravenous administration (see Figure 1). This is explained by the effects of ritonavir on the elimination inhibition of docetaxel.

Observations

[000145] This clinical study was conducted with relatively low doses of docetaxel, but yielding high AUC values (2.4 ± 1.5 mg.h/L; 100 mg docetaxel) and which were even higher than the AUC values after intravenous administration of the same dose. Thus, it was found that the volume of distribution via the oral route is greater (precisely after administration) than via the intravenous route because the pharmaceutical vehicle, present after intravenous administration but which does not reach the systemic circulation after oral administration, limits the tissue distribution of docetaxel. The inventors constructed a pharmacokinetic model to understand these effects (see below). The model also demonstrates that the effect of ritonavir on ritonavir elimination is lost when ritonavir is no longer present in the bloodstream. Ritonavir inhibits docetaxel clearance to 35% below the level in the absence of ritonavir.

[000146] Compared to the doses used in the prior art preclinical study in mice, this clinical study used 100 mg ritonavir and 100 mg docetaxel, while the preclinical study in mice used 12.5 mg/kg ritonavir and 10-30 mg/kg docetaxel. Docetaxel doses of 10-30 mg/kg are extremely toxic (life-threatening) in humans. Ritonavir doses of 12.5 mg/kg are substantially higher than would typically be used in humans to inhibit CYP3A4.

[000147] In the preclinical study of the prior art, ritonavir was administered 30 minutes before docetaxel. In the clinical study, the drugs were also administered simultaneously, with no difference in the improvement in docetaxel pharmacokinetics between simultaneous administration and 60 minutes before ritonavir administration. This indicates that both drugs can be provided in a single dosage form (e.g., tablet, capsule, or drinking solution containing docetaxel and ritonavir).

[000148] The AUC values for docetaxel (2.4 ± 1.5 mg.h/L) obtained (with the 100 mg docetaxel dose) when co-administered with 100 mg ritonavir can be considered therapeutically active on a weekly schedule in metastatic breast cancer. This compares well with a previous phase II clinical trial where 100 mg docetaxel was given orally with CsA at a dose of 15 mg/kg on a weekly schedule and leading to an overall response rate of 50% in metastatic breast cancer patients, with AUCs for docetaxel of approximately 2.3 mg.h/L.

[000149] Pharmacokinetic data for ritonavir are provided below until complete (see Figure 2):Table 2 – RITONAVIR

Pharmacokinetic profile

[000150] Pharmacokinetic (PK) analysis of the data generated from the above trial was performed using the NONMEM (non-linear mixed effect modeling) program (GloboMax LLC, Hanover, MD, USA) to produce a pharmacokinetic profile. This models the absorption, elimination, and distribution of a drug using different compartments. The pharmacological differences between oral and intravenous administration are presented below.

[000151] Exposure to oral docetaxel was examined after single doses of docetaxel alone and in combination with ritonavir. Ritonavir was administered simultaneously with or one hour before oral docetaxel.

[000152] After drug administration, blood samples were collected for pharmacokinetic analysis. A placebo sample was taken prior to dosing. The blood samples were centrifuged, the plasma was separated, and immediately stored at -20°C until analysis. The analysis was performed using validated HPLC methods in a licensed Good Laboratory Practice laboratory. This refers to all pharmacokinetic studies presented here by the inventors.

PK Model

[000153] The PK model was based on the PK model for i.v. docetaxel. This model uses three compartments and is well described by Bruno et al. [85]. Data generated from orally administered docetaxel were implemented within this model, adding additional storage compartment modeling for the gastrointestinal tract. The pharmacokinetic model for ritonavir was best described using a 2-compartment model, described by Kappelhoff et al. [87]. Figure 3 shows the final pharmacokinetic model schematically. The influence of ritonavir on docetaxel pharmacokinetics was modeled via two different mechanisms: a) enhancement of docetaxel absorption in the presence of ritonavir (lines relating ritonavir (RTV) compartments to docetaxel absorption from C1 to C2); b) ritonavir inhibits active CYP3A4 (line relating C6 to C7) and active CYP3A4 is responsible for the elimination of docetaxel (line relating C7 to the docetaxel elimination pathway).

Absorption

[000154] Docetaxel absorption was markedly improved when coadministered with ritonavir. The calculated bioavailability for oral docetaxel alone is 14% (based on data from 3 patients receiving 100 mg oral docetaxel). The bioavailability of oral docetaxel in combination with ritonavir was 4-fold greater, at 56%. This effect may be attributed to the inhibition of CYP3A4 enzymes present in the GI tract by ritonavir.

Elimination

[000155] Docetaxel is primarily metabolized by CYP3A4. Ritonavir inhibits CYP3A4. This results in decreased elimination when ritonavir is coadministered with docetaxel. Docetaxel clearance correlates with the amount of CYP3A4 and thus varies with time. Figure 4 shows the estimated relative enzyme concentration over time. Docetaxel clearance correlates 1:1 with enzyme concentration. Therefore, a graph of docetaxel clearance versus time would look similar to Figure 4.

Volume of distribution

[000156] The volume of the central compartment (C2 in Figure 3) differs markedly between i.v. (+/-6L) and oral (+/-60L) administration. This is likely due to polysorbate 80, one of the main excipients in the docetaxel formulation. Polysorbate 80 forms micelles which are able to entrap docetaxel [86]. Polysorbate 80 enters the circulation in the case of i.v. administration, but is not absorbed in the case of oral administration. Therefore, polysorbate does not affect the pharmacokinetic behavior of docetaxel after oral administration because it is not absorbed.

Conclusions

[000157] The bioavailability of oral docetaxel increased approximately 4-fold when co-administered with ritonavir. Systemic exposure, in terms of AUC, increased 8.2-fold due to the combined effect of ritonavir on CYP3A4 in the GI tract and liver (i.e., absorption and elimination, respectively).

[000158] Elimination of docetaxel is decreased when combined with ritonavir.

[000159] The volume of distribution (the volume of the central compartment) is small in the presence of polysorbate 80 and large without polysorbate 80.

[000160] In the above-mentioned oral docetaxel studies, the commercially available i.v. docetaxel formulation (Taxotere®; 2 ml = 80 mg docetaxel; excipient polysorbate 80) was diluted with 95% ethanol:water (13:87) to provide a 10 mg/ml docetaxel solution. This solution, prepared by a pharmacist, was ingested orally by patients (10 ml of the 10 mg/ml solution for a 100 mg dose) as a drinking solution combined with 100 ml of tap water. For research purposes, this is possible; however, it is not for routine home use. Preparation of the drinking solution by the pharmacist is time-consuming. The solution has limited stability. Patients often complain of an unpleasant and bad taste of the drinking solution (probably due to the excipients polysorbate and ethanol). Clearly, a solid oral dosage form (e.g., taken as a capsule or tablet) is preferred and much more pleasant for the patient.

[000161] In summary, the present invention improves the bioavailability and systemic exposure of taxanes, improves the clinical efficacy of taxanes, especially oral taxanes, and likely also reduces potential side effects associated with treatment. This is both economically and clinically beneficial.

Example 3 - Oral Paclitaxel Formulations 3.1: Solid dispersion versus physical mixing

[000162] In this experiment, the solubility and dissolution rate of a composition comprising a solid dispersion of paclitaxel and PVP-K17 mixed with SDS were compared with a physical mixture of anhydrous paclitaxel, PVP-K17 and SDS.

5 mg capsules of solid dispersions of paclitaxel in PVP-K17

[000163] A solid dispersion of 20% paclitaxel in PVP-K17 was prepared by dissolving 100 mg of paclitaxel in 10 mL of t-butanol and 400 mg of PVP-K17 in 6.67 mL of water. The paclitaxel/t-butanol solution was added to a PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3 for conditions). 25 mg of a solid dispersion of 20% paclitaxel/PVP-K17 (= 5 mg of paclitaxel) was mixed with 125 mg of Lactose, 30 mg of sodium dodecyl sulfate and 30 mg of croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 4).Table 3: Lyophilization conditions: Lyovac GT4 (AMSCO/Finn-Aqua) Table 4: Formulation of 5 mg capsules of paclitaxel/PVP-K17 solid dispersion

Paclitaxel 5 mg capsules in a physical mixture with PVP-K17

[000164] The physical mixture was prepared by mixing 5 mg anhydrous paclitaxel with 20 mg PVP, 125 mg lactose, 30 mg sodium dodecyl sulfate, and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated. Table 5: Formulation of 5 mg capsules of paclitaxel/PVP-K17 physical mixture

Dissolution test

[000165] Both capsule formulations were tested in 900 mL of Water for Injection maintained at 37°C in a USP 2 dissolution apparatus (paddle) with a rotation speed of 75 rpm. In the first experiment, one capsule of each formulation was used. In the second experiment, two capsules of each formulation were used. Samples were collected at various time points and analyzed by HPLC-UV (see Table 4).Table 6: Chromatographic conditions

Results and conclusions

[000166] The results are shown in Figure 5. The amount of dissolved paclitaxel is expressed relative to the labeling information (5 and 10 mg). It can be clearly seen that the dissolution of paclitaxel is greatly improved by incorporation into a solid dispersion with PVP. The maximum amount of dissolved paclitaxel remains below 20% relative to the labeling information when a physical mixture is used. When a solid dispersion is used, the solubility is about 65% (5 mg paclitaxel) or above 70% (10 mg paclitaxel). For the experiment with 10 mg paclitaxel, this corresponds to an absolute solubility of about 8 μg/ml and this is achieved after about 15 minutes. Therefore, the solid dispersion significantly increases the solubility and also provides a fast dissolution rate, both of which are important for bioavailability.

[000167] In a solid solution or solid dispersion, the amorphous state of the vehicle allows complete mixing of the vehicle and taxane. The vehicle prevents crystallization during storage as well as during dissolution in aqueous media.

3.2: Addition of sodium dodecyl sulfate to the capsule formulation

[000168] In this experiment, the effect of the presence or absence of SDS surfactant on the solubility of the capsule was determined.

Solid dispersion of 20% paclitaxel in PVP-K17

[000169] A solid dispersion was prepared by dissolving 100 mg of Paclitaxel in 10 mL of t-butanol and 400 mg of PVP-K17 in 6.67 mL of water. The paclitaxel/t-butanol solution was added to a PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Paclitaxel 5 mg capsules without sodium dodecyl sulfate

[000170] 25 mg of a 20% paclitaxel/PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose and encapsulated (see table 7).Table 7: Formulation of 5 mg capsules of paclitaxel/PVP-K17 solid dispersion without sodium dodecyl sulfate

Paclitaxel 5 mg capsules with sodium dodecyl sulfate

[000171] 25 mg of a 20% paclitaxel/PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose, 30 mg sodium dodecyl sulfate and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 8). Table 8: Formulation of 5 mg capsules of paclitaxel/PVP-K17 solid dispersion with sodium dodecyl sulfate

Dissolution test

[000172] Both capsule formulations were tested in 900 mL of Water for Injection maintained at 37°C in a USP 2 (paddle) dissolution apparatus with a rotation speed of 75 rpm. Samples were collected at various time points and analyzed by HPLC-UV (see Table 6).

Results and conclusions

[000173] The results are shown in Figure 6. The amount of paclitaxel dissolved is expressed relative to the information stated on the label (in this case, 5 mg). The porosity of the lyophilized solid dispersion of taxane and vehicle is high enough to ensure rapid dissolution when in powder form (results not shown). However, when the powder is compressed into capsules, the wettability is dramatically decreased. Therefore, a surfactant is required to wet the solid dispersion when it is compressed into tablets or capsules.

[000174] It can be clearly seen from Figure 6 that the dissolution of paclitaxel is greatly enhanced by the addition of the surfactant sodium dodecyl sulfate. Previous experiments had shown that the addition of croscarmellose sodium, more lactose, or the use of larger capsules does not result in increased dissolution rates of the capsule formulation. Again, this shows that with a surfactant such as SDS, maximum dissolution is achieved in about 10-15 minutes.

3.3: Addition of sodium dodecyl sulfate to the solid dispersion formulation

[000175] In this experiment, the effect of adding SDS to the solid dispersion on solubility was determined.

Solid dispersion of 40% paclitaxel in PVP-K17

[000176] A solid dispersion was prepared by dissolving 600 mg of Paclitaxel in 60 mL of t-butanol and 900 mg of PVP-K17 in 40 mL of water. The paclitaxel/t-butanol solution was added to the PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 40% paclitaxel in PVP-K17 and 10% sodium dodecyl sulfate

[000177] A solid dispersion was prepared by dissolving 250 mg of Paclitaxel in 25 mL of t-butanol and 375 mg of PVP-K17 and 62.5 mg of sodium dodecyl sulfate (SDS) in 16.67 mL of water. The paclitaxel/t-butanol solution was added to a PVP-K17/sodium dodecyl sulfate/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Paclitaxel/PVP-K17 solid dispersion 25 mg capsules

[000178] 62.5 mg of a 40% paclitaxel/PVP-K17 solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulfate and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 9).Table 9: Capsule formulation of 25 mg paclitaxel/PVP-K17 solid dispersion

Paclitaxel/PVP-K17/sodium dodecyl sulfate solid dispersion 25 mg capsules

[000179] 68.75 mg of a 40% paclitaxel/PVP-K17/10% sodium dodecyl sulfate solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 10).Table 10: Formulation of 25 mg capsules of paclitaxel/PVP-K17 solid dispersion

Dissolution test

[000180] Both capsule formulations were tested in 500 mL of Water for Injection maintained at 37°C in a USP 2 dissolution apparatus (paddle). The rotation speed was set at 75 rpm for the paclitaxel/PVP-K17/sodium dodecyl sulfate solid dispersion capsule and at 100 rpm for the paclitaxel/PVP-K17 solid dispersion capsule. Samples were collected at various time points and analyzed by HPLC-UV (see Table 6).

Results and conclusions

[000181] The results are shown in Figure 7. The amount of dissolved paclitaxel is expressed relative to the information stated on the label (in this case, 25 mg). It can be clearly observed that the dissolution of paclitaxel from capsules with sodium dodecyl sulfate incorporated into the solid dispersion is comparable to the dissolution of paclitaxel from capsules with sodium dodecyl sulfate added to the capsule. Furthermore, only 6.25 mg of sodium dodecyl sulfate was used for incorporation into the solid dispersion, whereas 30 mg of sodium dodecyl sulfate was used when added to the capsule formulation. This shows that less surfactant is required when it is incorporated into the solid dispersion rather than into the capsule in order to obtain similar results. Another surprising result from this experiment is that both compositions provide an absolute solubility of docetaxel of about 26 μg/ml, and this level is reached in 20-30 minutes. This result provides greater solubility and faster dissolution rate than previously obtained.

3.4: Vehicle influence

[000182] The solid dispersions used in the experiments of Example 3.4 were produced after initial experiments showed no clear differences between drug loadings. The 40% drug loading was selected because these formulations performed equally to the 20% drug loading formulation in the aforementioned experiments and offered the possibility of delivering more taxane in a tablet or capsule.

Solid dispersion of 40% paclitaxel in PVP-K12

[000183] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol and 375 mg of PVP-K12 in 16.67 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K12 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 40% paclitaxel in PVP-K17

[000184] A solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60 mL of t-butanol and 900 mg of PVP-K17 in 40 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K17 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 40% paclitaxel in PVP-K30

[000185] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol and 375 mg of PVP-K30 in 16.67 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K30 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 40% docetaxel in HP-cyclodextrin

[000186] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol and 375 mg of HP-cyclodextrin in 16.67 mL of water. The paclitaxel/t-butanol solution was added to the aqueous HP-cyclodextrin solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Paclitaxel solid dispersion 25 mg capsules

[000187] 62.5 mg of the solid paclitaxel/vehicle dispersion (= 25 mg of paclitaxel) was mixed with 160 mg of lactose, 30 mg of sodium dodecyl sulfate and 10 mg of croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 11).Table 11: Formulation of 25 mg capsules of solid paclitaxel/vehicle dispersion

Dissolution test

[000188] All capsule formulations were tested in 500 mL of Water for Injection maintained at 37°C in a USP 2 (paddle) dissolution apparatus with a rotation speed of 100 rpm. Samples were collected at various time points and analyzed by HPLC-UV (see Table 6).

Results and conclusions

[000189] The average results of 2 to 3 experiments are shown in Figure 8. The amount of dissolved paclitaxel is expressed relative to the information stated on the label (in this case 25 mg). It can be clearly seen that the dissolution of paclitaxel from a solid dispersion in PVP-K30 is as fast as the dissolution of paclitaxel from a solid dispersion in PVP-K17. However, the amount of dissolved paclitaxel remains higher throughout the 4 hour experiment in the case of a solid dispersion in PVP-K30.

[000190] The chain length of the polymeric carrier determines the time for crystallization in aqueous environments.

3.5: Influence of drug/vehicle ratio

[000191] The solid dispersions used in the experiments of Example 3.5 were produced after initial experiments showed no clear differences between the vehicles. These initial experiments were done before the more detailed experiments of Example 3.4. As a result, PVP-K17 was arbitrarily chosen as a vehicle for further experiments.

Solid dispersion of 10% paclitaxel in PVP-K17

[000192] A solid dispersion was prepared by dissolving 100 mg of paclitaxel in 10 mL of t-butanol and 900 mg of PVP-K17 in 40 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K17 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 25% paclitaxel in PVP-K17

[000193] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol and 750 mg of PVP-K17 in 16.67 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K17 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 40% paclitaxel in PVP-K17

[000194] A solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60 mL of t-butanol and 900 mg of PVP-K17 in 6.67 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K17 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Solid dispersion of 75% paclitaxel in PVP-K17

[000195] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol and 83 mg of PVP-K17 in 16.67 mL of water. The paclitaxel/t-butanol solution was added to an aqueous solution of PVP-K17 under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

100% paclitaxel solid dispersion

[000196] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol. The paclitaxel/t-butanol solution was added to 16.67 mL of water under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Dissolution test

[000197] An amount of solid dispersion powder, equal to approximately 4 mg of Paclitaxel, was placed in a 50 mL beaker. A magnetic stir bar and 25 mL of water were added to the beaker. The solution was stirred at 7200 rpm. Samples were collected at various time points and analyzed by HPLC-UV (see Table 6).

Results and Conclusions

[000198] The average results of 2 to 3 experiments are shown in Figure 9. The amount of paclitaxel (PCT) dissolved is expressed relative to the information stated on the label (in this case, approximately 4 mg). The influence of the drug/vehicle ratio is immediately evident from Figure 9. The peak concentration value of paclitaxel is inversely related to the drug/vehicle ratio. The highest peak concentration is achieved at a lower drug/vehicle ratio (10%), while the lowest peak concentration is achieved at the higher drug/vehicle ratio (100%). Furthermore, the AUC values of the 10% drug/vehicle solid dispersion are the highest, followed by the AUC values of 25, 40, 75, and 100% drug/vehicle solid dispersions.

[000199] The amount of vehicle relative to the amount of drug determines the time for crystallization in aqueous environments.

3.6: Influence of enteric coating Solid dispersion of 40% paclitaxel in PVP-K17 and 10% sodium dodecyl sulfate

[000200] A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol and 375 mg of PVP-K17 and 62.5 mg of sodium dodecyl sulfate (SDS) in 16.67 mL of water. The paclitaxel/t-butanol solution was added to a PVP-K17/sodium dodecyl sulfate/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilization (see Table 3).

Paclitaxel/PVP-k17/sodium dodecyl sulfate 25 mg solid dispersion capsules

[000201] 68.75 mg of a solid dispersion of 20% paclitaxel/PVP-K17/10% sodium dodecyl sulfate (= 25 mg paclitaxel) was mixed with 160 mg lactose and 10 mg croscarmellose sodium.Table 12: Capsule formulation with 25 mg paclitaxel/PVP-K17/SDS solid dispersion

Dissolution Test

[000202] The capsules were subjected to two different dissolution tests in pairs. The first test was a pipeline dissolution test, consisting of two-hour dissolution testing in 500 mL of simulated gastric fluid without pepsin (SGFsp; see Table 13), followed by two-hour dissolution testing in 629 mL of simulated intestinal fluid without pepsin (SIFsp; see Table 13). The second test was conducted in 500 mL of simulated intestinal fluid medium in a fasted state (FaSSIF; see Table 14) for four hours.

[000203] Both dissolution tests were performed in a USP 2 dissolution apparatus (paddle) with 500 mL of medium maintained at 37°C and a paddle rotation speed of 75 rpm. SGFsp medium was exchanged for SIFsp medium by adding 129 mL of exchange medium. Samples were collected at various time points and analyzed by HPLC-UV (see Table 6).Table 13: SGFsp, SIFsp, and Exchange Medium [96] Table 14: Fasted State Simulated Intestinal Fluid Medium (FaSSIF) [97]

Results and conclusions

[000204] The results are shown in Figure 10. The amount of paclitaxel dissolved is expressed relative to the information stated on the label (in this case 25 mg). The dissolution of paclitaxel in simulated intestinal fluid in the fasted state is approximately 20% greater than in simulated gastric fluid (SGFsp). After two hours in SGFsp, the amount of paclitaxel in solution is only slightly increased when the medium is switched to simulated intestinal fluid (SIFsp).

[000205] An enteric coating will prevent release of the taxane in the stomach, thereby preventing degradation of the active components. Furthermore, it will allow targeted delivery to the intestine, where the taxane is absorbed, thus ensuring that the limited time the taxane is present in solution (before crystallization occurs) is consumed only at sites where absorption is possible.

Example 4 - Oral formulations of docetaxel Materials and methods

[000206] The formulations used in the following experiments were prepared according to the procedures outlined below and the compositions represented in Table 15.

Pure anhydrous docetaxel

[000207] Anhydrous docetaxel was used as obtained from ScinoPharm, Taiwan.

Pure amorphous docetaxel

[000208] Docetaxel was rendered amorphous by dissolving 300 mg of docetaxel anhydrate in 30 mL of t-butanol. The docetaxel/t-butanol solution was added to 20 mL of Water for Injection (WfI) under constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9), and t-butanol and water were subsequently removed by lyophilization (see Table 16).

Physical mixtures

[000209] Physical mixtures were prepared by mixing 150 mg of docetaxel and corresponding amounts of vehicle and surfactant (see Table 15) with a pestle and mortar.

Solid dispersions

[000210] Solid dispersions were obtained by dissolving 300 mg of docetaxel anhydrate in 30 mL of t-butanol and corresponding amounts of vehicle and surfactant (see Table 15) in 20 mL of Water for Injection. The docetaxel/t-butanol solution was added to the vehicle/surfactant/WfI solution under constant stirring. The final mixture was transferred to a stainless steel freeze-drying box (Gastronorm size 1/9), t-butanol and water were subsequently removed by freeze-drying (see Table 16).Table 15: Composition of the tested formulations Table 15 – continued 1 HPβ-CD is hydroxypropyl-β-cyclodextrinTable 16: Lyophilization conditions

Dissolution test

[000211] An amount of powder, equal to approximately 6 mg of Docetaxel, was placed in a 50 mL beaker. A magnetic stir bar and 25 mL of water were added to the beaker. The solution was stirred at 720 rpm and maintained at approximately 37 °C. Samples were collected at various time points and filtered using a 0.45 μm filter before being diluted with a 1:4 v/v mixture of methanol and acetonitrile. The filtered and diluted samples were subsequently analyzed by HPLC-UV (see Table 17).Table 17: Chromatographic conditions

4.1: Formulation type

[000212] In the first experiment, the influence of formulation type on docetaxel solubility was examined. Data from the dissolution test performed on formulations A and E were compared. The results are shown in Figure 11. Formulation E was tested in quadruplicate, formulations A to D were tested in duplicate.

Results

[000213] Formulation A (pure docetaxel anhydrate) reaches a maximum concentration of approximately 12 μg/mL (4.7% total docetaxel present) after 5 minutes of shaking and reaches an equilibrium concentration of approximately 6 μg/mL (2%) after 15 minutes of shaking.

[000214] Formulation B (pure amorphous docetaxel) reaches a maximum of 32 μg/mL (13%) after 0.5 minutes, from 10 to 60 minutes the solubility is comparable to formulation A.

[000215] Formulation C (physical mixture of anhydrous docetaxel, PVP-K30 and SDS) reaches a concentration of approximately 85 μg/mL (37%) after 5 minutes. Between 15 and 25 minutes, the docetaxel concentration declines sharply from 85 μg/mL (37%) to 30 μg/mL (12%), after which it further declines to 20 μg/mL (9%) at 60 minutes.

[000216] Formulation D (physical mixture of amorphous docetaxel, PVP-K30 and SDS) reaches a maximum docetaxel concentration of 172 μg/mL (70%) after 7.5 minutes. Between 7.5 and 20 minutes, the amount of docetaxel in solution drops to 24 μg/mL (10%). At 60 minutes, the equilibrium concentration of 19 μg/mL (7%) is reached.

[000217] Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has the highest maximum concentration of 213 μg/mL (90%), which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution declines rapidly, resulting in an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.

Conclusions

[000218] All formulations initially show increased solubility, which decreases to equilibrium solubility after 45 to 60 minutes of stirring. The decrease in solubility is caused by the crystallization of docetaxel as a result of the supersaturated solution. The degree of supersaturation depends on the physical state of the drug, i.e., whether it is amorphous or crystalline. When PVP-K30 is the vehicle, the supersaturated state is maintained for a longer time, so the solubility of docetaxel does not decrease as rapidly. Furthermore, the results show that the use of amorphous docetaxel significantly increases the solubility of docetaxel compared to anhydrous docetaxel. Furthermore, amorphous docetaxel shows a relatively high dissolution rate, reaching a peak around 5 to 7.5 minutes.

[000219] This experiment shows that the amount of docetaxel in solution is markedly increased by physically mixing anhydrous docetaxel with PVP-K30 and SDS and even more so by physically mixing amorphous docetaxel with PVP-K30 and SDS. The greatest increase in solubility, however, is obtained by incorporating docetaxel into a solid dispersion of PVP-K30 and SDS.

4.2: Vehicle type

[000220] In the second experiment, the influence of vehicle type on docetaxel solubility was examined. Data from the dissolution test performed with formulations E and F were compared. The results are shown in Figure 12. Formulation E was tested in quadruplicate, formulation F was tested in duplicate.

Results

[000221] Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has a higher maximum concentration of 213 μg/mL (90% of the total docetaxel present), which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution declines rapidly, resulting in an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.

[000222] Formulation F (solid dispersion of amorphous docetaxel, HPβ-CD and SDS) reaches a maximum docetaxel concentration of approximately 200 μg/mL (81%) after about 2 minutes. Between 5 and 10 minutes, the amount of docetaxel in solution drops to a value of 16 μg/mL (6%), and after 45 minutes, an equilibrium concentration of 11 μg/mL (4%) is reached.

Conclusions

[000223] This experiment shows that PVP-K30 and HPβ-CD increase the solubility of docetaxel. When PVP-K30 is used as the vehicle compared to HPβ-CD, the maximum docetaxel concentration is slightly higher and the supersaturation state is maintained longer, so that docetaxel solubility does not decrease as rapidly with time. Furthermore, the equilibrium concentration reached after docetaxel precipitation is higher with PVP-K30 compared to HPβ-CD.

4.3: Chain length

[000224] In the third experiment, the influence of PVP chain length on docetaxel solubility was examined. Data from the dissolution test performed on formulations E and G to J were compared. The results are shown in Figure 13. Formulation E was tested in quadruplicate, formulations G to J were tested in duplicate.

Results

[000225] Formulation G (PVP-K12) reaches a maximum docetaxel concentration of 206 μg/mL (77% of the total docetaxel present) after 5 minutes. Between 5 and 30 minutes, the amount of docetaxel in solution decreases to 20 μg/mL (7%), and at 45 minutes, the docetaxel concentration is 17 μg/mL (6%).

[000226] Formulation H (PVP-K17) reaches a maximum docetaxel concentration of 200 μg/mL (83%) after 5 minutes and maintains this concentration until 10 minutes of shaking, after which the amount of docetaxel in solution rapidly drops to 44 μg/mL (18%) at 15 minutes and 22 μg/mL (9%) at 30 minutes. The equilibrium concentration between 45 and 60 minutes is approximately 21 μg/mL (8%).

[000227] Formulation I (PVP-K25) reaches a maximum docetaxel concentration of 214 μg/mL (88%) after 5 minutes of shaking. The amount of docetaxel in solution decreases between 10 and 30 minutes to 22 μg/mL (9%) and at 60 minutes the docetaxel concentration is 19 μg/mL (8%).

[000228] Formulation E (PVP-K30) has a maximum docetaxel concentration of 213 μg/mL (90%), which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution declines rapidly, resulting in an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.

[000229] Formulation J (PVP-K90) reaches a maximum docetaxel concentration of 214 μg/mL (88%) after 10 minutes of shaking. At 15 minutes, the amount of docetaxel in solution is still 151 μg/mL (61%). After 60 minutes, the docetaxel concentration has declined to 19 μg/mL (7%).

Conclusions

[000230] This experiment shows that the chain length of PVP influences the degree of supersaturation and the period of supersaturation is maintained. The use of PVP with longer chain lengths results in higher maximum docetaxel concentrations and a longer period of supersaturation, thus greater solubility over a longer period of time.

4.4: Drug loading

[000231] In the fourth experiment, the influence of drug loading on the solubility of docetaxel was examined. Data from dissolution tests performed on formulations E and K to N were compared. The results are shown in Figure 14. Formulation E was tested in quadruplicate, formulations K to N were tested in duplicate.

[000232] Formulation N (1/21 docetaxel by weight of the total composition; 5:95 weight/weight docetaxel to PVP) reaches a maximum docetaxel concentration of 197 μg/mL (79% of the total docetaxel present) after 10 minutes. After 15 minutes, the amount of docetaxel in solution is still 120 μg/mL (48%), and between 15 and 30 minutes, the docetaxel concentration decreases to 24 μg/mL (12%). At 60 minutes, the docetaxel concentration is 20 μg/mL (8%).

[000233] Formulation E (1/11 docetaxel by weight of the total composition; 10:90 weight/weight docetaxel to PVP) has a maximum concentration of 213 μg/mL (90%), which is reached after 5 minutes. Between 10 and 30 minutes, the amount of docetaxel in solution declines rapidly and reaches an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.

[000234] Formulation M (1/6 docetaxel by weight of the total composition; 20:80 weight/weight docetaxel to PVP) has a docetaxel concentration of 196 μg/mL (80%) after 10 minutes of shaking. The amount of docetaxel in solution decreases between 10 and 30 minutes to 25 μg/mL (10%), and at 60 minutes the docetaxel concentration is 18 μg/mL (7%).

[000235] Formulation L (1/3 docetaxel by weight of the total composition; 40:60 weight/weight docetaxel to PVP) achieves a docetaxel concentration of 176 μg/mL (71%). Between 10 and 15 minutes, the amount of docetaxel in solution drops rapidly to 46 μg/mL (18%), and after 60 minutes, the amount of docetaxel in solution is 18 μg/mL (7%).

[000236] Formulation K (5/7 docetaxel by weight of total composition; 75:25 weight/weight docetaxel to PVP) reaches a maximum docetaxel value of 172 μg/mL (71%) after 5 minutes of shaking. Between 5 and 10 minutes, the docetaxel concentration declines sharply to 42 μg/mL (17%), and after 60 minutes, a docetaxel concentration of 18 μg/mL (7%) is reached.

Conclusions

[000237] This experiment shows that the amount of PVP-K30 relative to the amount of docetaxel used in the solid dispersions influences the degree of supersaturation and the period of supersaturation is maintained. The use of higher drug loadings results in lower maximum docetaxel concentrations and a shorter period of supersaturation, thus in a lower solubility over time.

4.5: Solubility comparison with a prior art composition

[000238] In this experiment, a composition containing a solid dispersion of 15 mg docetaxel, 135 mg PVP-K30, and 15 mg SDS was compared with literature data for a composition comprising a solid dispersion of 5 mg docetaxel and PVP-K30 as disclosed in Chen et al. [95]. Solubility results were obtained using the dissolution test described in Chen et al. [95] and are shown in Figures 15 and 16. A dissolution test was also conducted in Simulated Intestinal Fluid and compared with Chen's literature data. The results are shown in Figure 17.

Results

[000239] From Figure 15, it can be seen that the composition of Chen et al. can dissolve a maximum of about 80% of the 5 mg of docetaxel in the composition in 900 ml of water. It took more than 5 hours to reach this maximum. The composition of docetaxel, PVP-K30, and SDS dissolved 100% of the 15 mg of docetaxel in about 60 minutes.

[000240] In Figure 16, the absolute concentration of docetaxel is provided. Chen's composition provided a maximum docetaxel concentration of about 4.2 μg/ml after about 5 hours. The composition of docetaxel, PVP-K30, and SDS provided a maximum docetaxel concentration of about 16.7 μg/ml after about 60 minutes.

[000241] In Figure 17, docetaxel capsules achieve a solubility of 28 μg/ml (solubility >90%). The solid dispersion described by Chen et al. (docetaxel + PVP K30) achieves a solubility of 4.2 μg/ml (less than 80% of the 5 mg docetaxel solid dispersion tested with respect to dissolution in 900 ml). The capsule formulation thus achieves 6.6-fold better solubility, with a higher dissolution rate (maximum achieved after 30 minutes versus 90-120 minutes by Chen).

Conclusions

[000242] From these results, it can be seen that the composition of docetaxel, PVP-K30 and SDS provided a faster dissolution rate and a higher solubility compared to Chen's composition. For bioavailability, it is important to know how fast a drug dissolves and what solubility is reached in 0.5 to 1.5 h.

[000243] From Chen's results, those skilled in the art will not consider that increasing the amount of docetaxel in the composition would increase the absolute solubility of docetaxel. Since Chen's composition dissolves only 80% of 5 mg of docetaxel (i.e., 4 mg) in 900 ml of water, one would not expect that increasing the amount of docetaxel to 15 mg would cause more than 4 mg of docetaxel to dissolve. Thus, a 15 mg docetaxel composition according to Chen would be expected to dissolve a maximum of about 27% of the docetaxel compared to 100% for the docetaxel, PVP-K30, and SDS composition. Therefore, the docetaxel, PVP-K30, and SDS composition provides surprisingly good results compared to Chen.

4.6: Dissolution test in simulated intestinal fluid sine pancreatin (SIFsp)

[000244] In this experiment, the dissolution of capsules containing a solid dispersion of docetaxel, PVP-K30, and SDS was tested in Simulated Intestinal Fluid without Pancreatin (SIFsp). The capsules contained 15 mg of docetaxel according to formulation E (see Table 15). SIFsp was prepared according to USP 28. Capsules containing 15 mg of docetaxel were dissolved in 500 mL of SIFsp USP at 37 °C with shaking at 75 rpm. The results are shown in Figures 18 and 19.

[000245] Figures 18 and 19 show that approximately 100% of the docetaxel has dissolved. This is equivalent to an absolute docetaxel concentration of about 29 μg/ml and is achieved in about 30 minutes. Thus, the composition provides relatively high solubility in a relatively short period of time.

4.7: Stability

[000246] The solid dispersion of docetaxel, PVP-K30 and SDS according to formulation E (see table 15) and which was used in capsules for clinical trials (see Example below) was found to be chemically (no degradation) and physically (no change in solubility characteristics) stable for at least 80 days when stored at 4-8°C.

Example 5: Clinical trial data with formulations Materials and methods

[000247] 10 patients participated in an ongoing Phase I clinical trial.

[000248] These patients were provided with the following numbers:

[000249] 301, 302, 303, 304, 305, 306, 307, 308, 309 and 310.

[000250] These patients were provided with a medication which consisted of a liquid formulation of docetaxel or a solid composition comprising a solid dispersion of docetaxel, PVP-K30 and SDS (referred to hereinafter as MODRA).

Liquid formulation

[000251] Docetaxel dose: 30 mg for all patients (except patient 306, who received 20 mg docetaxel). The 30 mg dose was prepared as follows: 3.0 mL of Taxotere® premix for intravenous administration (containing 10 mg docetaxel per mL in polysorbate 80 (25% v/v), ethanol (10% (w/w) and water) was mixed with water to a final volume of 25 mL. This solution was orally ingested by the patient with 100 mL of tap water.

MODRA

[000252] Docetaxel dose: 30 mg; 2 capsules with 15 mg docetaxel per capsule were ingested. Formulation E from the previous example (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) was selected for further testing in the clinical trial. A new batch of formulation E was produced by dissolving 1200 mg docetaxel anhydrate in 120 mL t-butanol and 10800 mg PVP-K30 and 1200 mg SDS (see Table 15) in 80 mL Water for Injection. The docetaxel/t-butanol solution was added to a PVP-K30/SDS/WfI solution under constant stirring. The final mixture was transferred to a stainless steel freeze-drying box (1/3 Gastronorm size), t-butanol and water were subsequently removed by freeze-drying (see Table 16).

[000253] A total of 60 size 0 gelatin capsules were filled with an amount of solid dispersion equivalent to 15 mg of docetaxel, an HPLC assay was used to determine the exact amount of docetaxel per mg of solid dispersion. The assay confirmed that the capsules contained 15 mg of docetaxel.

[000254] Patients took the medication orally on an empty stomach in the morning with 100 mL of running water.

Patient treatment

[000255] Patients 301, 302, 303, 304, and 305 received liquid formulation only.

[000256] 306 patients received 20 mg docetaxel as a liquid formulation + ritonavir in the first cycle and, in the second cycle, the same medication but with extra ritonavir 4 hours after docetaxel intake.

[000257] Patients 307, 308, 309, and 310 received liquid formulation and/or MODRA. Cycles were administered at a weekly interval.

[000258] In accordance with institutional guidelines, for oral and i.v. docetaxel, all patients were treated with oral dexamethasone. A 4 mg dose of dexamethasone was given 1 hour before study drugs, followed by 4 mg every 12 hours (b.i.). One hour before docetaxel treatment, patients also received 1 mg of granisetron (Kytril®) to prevent nausea and vomiting.

[000259] After drug administration, blood samples were collected for pharmacokinetic analyses. A placebo sample was taken prior to dosing. Blood samples were centrifuged, plasma was separated, and immediately stored at -20°C until analysis. Analyses were performed with validated HPLC methods in a certified GLP (Good Laboratory Practice) laboratory [101]. Results Table 18 provides an overview of the individual pharmacokinetic results.

[000260] docLF: docetaxel liquid formulation

[000261] MODRA: docetaxel capsule formulation

[000262] Last: time at which the last sample for measurement of docetaxel concentration was taken (in h)

[000263] Conc ultimate: docetaxel concentration in Túltima (in ng/mL)

[000264] AUC last: AUC calculated up to the last Conc (ng.h/mL)

[000265] AUC inf: AUClast + extrapolation to infinity (ng.h/mL)

[000266] The dosage of ritonavir is, in all cases, 100 mg (capsule, Norvir®)

[000267] Patients 301, 302, 303, 304, 305, 307, 309, and 310 received the liquid formulation. The mean and 95% confidence interval for the mean AUC (extrapolated to infinity) is: 1156 (+ 348) ng*h/mL. Interindividual variability is 85%.

[000268] Patient 306 received 20 mg docetaxel (as liquid formulation) concomitantly with 100 mg ritonavir in the first cycle and the same combination one week later in the second cycle, but with an extra 100 mg ritonavir 4 hours after docetaxel intake, i.e. two doses of ritonavir were taken, one at t = 0 and the second at t = 4 h. The pharmacokinetic curves are represented in Figure 20.

[000269] Patients 307, 308, 309, and 310 received liquid formulation and/or MODRA. The pharmacokinetic curves are depicted in Figure 21.

[000270] Figure 22 depicts the pharmacokinetic curves of patients receiving the liquid formulation (307, 309, and 310) and all courses (n = 6) of the four patients receiving MODRA (307, 308, 309, and 310).

[000271] The pharmacokinetic results of the liquid formulation versus MODRA, both in combination with 100 mg ritonavir, are summarized below:

Liquid formulation (30 mg docetaxel)

[000272] AUCinf (95% confidence interval of the mean): 1156 (808-1504) ng*h/ml

[000273] Interindividual variability: 85% (n = 8)

MODRA (30 mg docetaxel)

[000274] AUCinf (95% confidence interval of the mean): 768 (568968) ng*h/ml

[000275] Interindividual variability: 29% (n = 4)

[000276] Intraindividual variability: 33% (n = 2

[000277] The mean AUC of MODRA was calculated using the 6 curves from four patients. The first dose of MODRA administered to each patient was used to calculate inter-individual variability. Intraindividual variability is based on data from patients 307 and 308 who received two doses of MODRA.

Conclusions

[000278] The liquid formulation of docetaxel tested results in an AUC value that is approximately 1.5 times higher than the same dose (30 mg) provided in the new capsule formulation (MODRA)

[000279] The inter-subject variability of the liquid formulation is high (85%), while the inter-subject variability of the capsule formulation is substantially lower (29%). This is an important feature of the new capsule formulation and provides a much more predictable exposure to docetaxel. Also, for safety reasons, low inter-subject variability is highly desired in oral chemotherapy regimens.

[000280] Interindividual variability (limited data) is of the same order of magnitude as interindividual variability.

[000281] A second booster dose of 100 mg ritonavir taken 4 hours after docetaxel administration increases docetaxel AUC 1.5-fold.

Comparison of oral capsule formulations with i.v. administration

[000282] Figure 23 shows the pharmacokinetic curves after i.v. (20 mg docetaxel as a 1-hour i.v. infusion, Taxotere®) (n = 5 patients) and oral docetaxel (30 mg docetaxel; MODRA capsules, see above) (n = 4 patients; 6 courses) administration. I.v. and oral docetaxel administration were combined with 100 mg ritonavir (capsule, Norvir®) administration. In accordance with institutional guidelines, for both oral and i.v. docetaxel, all patients were treated with oral dexamethasone. A 4 mg dose of dexamethasone was given 1 hour before the study drugs, followed by 4 mg every 12 hours (b.i.). One hour before docetaxel treatment, patients also received 1 mg of granisetron (Kytril®) to prevent nausea and vomiting.

[000283] The bioavailability of MODRA capsules was calculated using:

[000284] (AUC of 30 mg oral / AUC of 20 mg iv) x (20 / 30) x 100%

[000285] = 73% (SD 18%).

[000286] This shows that the bioavailability of the capsules is relatively high, with low inter-individual variability.

[000287] The preceding Examples are intended to illustrate specific embodiments of the present invention and are not intended to limit the scope thereof, the scope being defined by the appended claims. All documents cited herein are incorporated herein by reference in their entirety. References 1. Demario MD, Ratain MJ. Oral chemotherapy: rationale and future directions. J Clin Oncol 1998; 16: 2557-2567. 2. Liu G, Franssen E, Fitch MI et al. Patient preferences for oral versus intravenous palliative therapy. J Clin Oncol 1997; 15: 110-115. 3. Meerum Terwogt JM, Beijnen JH, ten Bokkel Huinink WW et al. Co-administration of cyclosporin A enables oral therapy with paclitaxel. Lancet 1998; 352: 285. 4. Sparreboom A, van Asperen J, Mayer U, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 1997; 94: 2031-2035.5. Kuhn J, Rizzo J, Eckhardt J, et al. Phase I bioavailability study of oral topotecan. Proc Am Soc Clin Oncol 1995; 14:474.6. Schellens JHM, Creemers GJ, Beijnen JH and others. Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase inhibitor. Br J Cancer 1996; 73: 1268-1271.7. Hellriegel ET, Bjornnson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther 1996; 60: 601-607.8. Huizing MT, Giaccone G, van Warmerdam LJC, et al. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and sequencing study in patients with non-small cell lung cancer. J Clin Oncol 1997; 15: 317-329.9. Van Asperen J, van Tellingen O, Beijnen JH, et al. The pharmacological role of P-glycoprotein in the intestinal epithelium. Pharmacol Res 1998; 37: 429-435.10. Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84: 7735-7738.11. Fojo AT, Ueda K, Slamon DJ and others. Expression of a multidrug resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 1987; 84: 265-269.12. Van Asperen J, Mayer U, van Tellingen O, et al. The pharmacological role of P-glycoprotein in the blood-brain barrier. J Pharm Sci 1997; 86:881-884.13. Tsuruo T, Iida H, Tsukagoshi S, et al. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 1981; 41: 1967-1972.14. Ford JM, Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 1990; 42: 155-199.15. Slater LM, Sweet P, Stupecky M and others. Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J Clin Invest 1986; 77: 1405-1408.16. Hyafil F, Vergely C, Du Vignaud P, et al. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res 1993; 53:4595-4602.17. Van Zuylen L, Sparreboom A, Van der Gaast A, et al. The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel. Clin Cancer Res 2000; 6: 1365-1371.18. Dantzig AH, Shepard RL, Cao J, et al. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res 1996; 56:4171-4179.19. Relling MV. Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs? Ther Drug Monitor 1996; 18: 350-356.20. Lum BL, Fisher GA, Brophy NA and others. Clinical trials of modulation of multidrug resistance: pharmacokinetic and pharmacodynamic considerations. Cancer 1993; 72(suppl 11): 3502-3514.21. Dalton WS, Crowley JJ, Salmon SS and others. A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma: a Southwest Oncology Group Study. Cancer 1995; 75: 815-820.22. Milroy R. A randomized clinical study of verapamil in addition to combination chemotherapy in small cell lung cancer. West of Scotland Lung Cancer research Group and the Aberdeen Oncology Group. Br J Cancer 1993; 68: 813-818.23. Wishart GC, Bissett D, Paul J, et al. Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo controlled randomized trial. J Clin Oncol 1994; 12: 1771-1777.24. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog1995; 13: 129-134.25. Watkins PB. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv Drug Deliv Rev 1997; 27: 161-170. 26. Wacher VJ, Silverman JA, Zhang Y et al. Role of P- glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998; 87: 1322-1330.27. Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002; 300: 1036-1045.28. De Bruin M, Miyake K, Litman K, et al. Reversal of resistance by GF120918 in cell lines expressing the half transporter, MXR. Cancer Lett 1999; 146: 117-126.29. Maliepaard M, van Gastelen MA, Tohgo A, et al. Circumvention of BCRP-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res 2001; 7: 935-941.30. Guengerich FP. In vitro techniques for studying drug metabolism. J Pharmacokinet Biopharm 1998; 24: 521-533.31. Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998; 35: 361-390.32. Watkins PB, Wrighton SA, Schuetz EG, et al. Identification of glucocorticoid-inducible cytochromes P450 in the intestinal mucosa of rats and man. J Clin Invest 1987; 80: 1029-1036.33. Lown KS, Kolars JC, Thummel KE. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos 1994; 22: 947-955.34. Huizing MT, Misser VH, Pieters RC and others. Taxanes: a new class of antitumor agents. Cancer Invest 1995; 13: 381-404.35. Fujita H, Okamoto M, Takao A, et al. Pharmacokinetics of paclitaxel in experimental animals. Part 1. Blood levels. Gan To Kagaku Ryoho 1994; 21: 653-658. 36. Eiseman JL, Eddington ND, Leslie J et al. Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice. Cancer Chemother Phamacol 1994; 34: 465-471.37. Rowinsky EK, Wright M, Monsarrat B, et al. Clinical pharmacology and metabolism of taxol (paclitaxel): update 1993. Ann Oncol 1994; 5(suppl 6): S7-S16.38. Sonnichsen DS, Liu Q, Schuetz EG, et al. Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol Exp Ther 1995; 275: 566-575.39. Walle T, Walle K, Kumar GN, et al. Taxol metabolism and disposition in cancer patients. Drug Metabol Dispos 1995; 23: 506-512.40. Sparreboom A, van Tellingen O, Nooijen WJ, et al. Preclinical pharmacokinetics of paclitaxel and docetaxel. Anticancer Drugs 1998; 1:1-17.41. Van Asperen J, van Tellingen O, Sparreboom A, et al. Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer 1997; 76:11811183.42. Van Asperen J, van Tellingen O, van der Valk MA, et al. Enhanced oral absorption and decreased elimination of paclitaxel in mice with cyclosporin A. Clin Cancer Res 1998; 4:2293-2297.43. Harris JW, Rahman A, Kim BR, et al. Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res 1994; 54: 4026-4035.44. Cresteil T, Monsarrat B, Alvinerie P et al. Taxol metabolism by human liver microsomes: identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 1994; 54: 386-392.45. Webber IR, Peters WH, Back DJ. Cyclosporin metabolism by human gastrointestinal mucosal microsomes. Br J Clin Pharmacol 1992; 33: 661-664.46. Bardelmeijer HA, Beijnen JH, Brouwer KR et al. Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin Cancer Res 2000; 6:4416-4421.47. Wils P, Phung-Ba V, Warnery A, et al. Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochem Parmacol 1994; 48: 1528-1530.48. Shirakawa K, Takar K, Tanigawara Y, et al. Interaction of docetaxel (Taxotere) with human P-glycoprotein. Jpn J Cancer Res 1999; 90: 1380-1386.49. Bardelmeijer HA, Ouwehand M, Buckle T, et al. Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir. Proc Am Assoc Cancer Res 2002; 43: 262 and Cancer Research 2002; 62: 6158-6164.50. Marre F, Sanderink GJ, Desousa G et al. Hepatic biotransformation of docetaxel (taxotere) in vitro: involvement of the CYP3A subfamily in humans. Cancer Res 1996; 56: 1296-1302.51. Meerum Terwogt JM, Malingré MM, Beijnen JH et al. Coadministration of cyclosporin enables oral therapy with paclitaxel. Clin Cancer Res 1999; 5:3379-3384.52. Malingré MM, Terwogt JM, Beijnen JH et al. A phase I and pharmacokinetic study of oral paclitaxel. J Clin Oncol 2000; 18: 2468-2475.53. Malingré MM, Schellens JHM, van Tellingen O et al. Metabolism and excretion of paclitaxel after oral administration in combination with cyclosporin A and after intravenous administration. Anticancer Drugs 2000; 11: 813-820.54. Gianni L, Kearns CM, Giani A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its phamacokinetic/pharmacodynamic relationship in humans. J Clin Oncol 1995; 13: 180-190.55. Sparreboom A, van Tellingen O, Nooijen WJ, et al. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs 1996; 7: 78-86.56. van Tellingen O, Huizing MT, Panday VR, et al. Cremophor EL causes (pseudo) nonlinear pharmacokinetics of paclitaxel in patients. Br J Cancer 1999; 81: 330-335.57. Malingré MM, Beijnen JH, Rosing H et al. A phase I and pharmacokinetic study of bidaily dosing of oral paclitaxel in combination with cyclosporin A. Cancer Chemother Pharmacol 2001; 47: 347-354.58. Malingré MM, Beijnen JH, Rosing H et al. The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel. Anticancer Drugs 2001; 12: 351-358.59. Malingré MM, Beijnen JH, Rosing H et al. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer 2001; 84: 42-47.60. Kruijtzer CMF, Schellens JHM, Mezger J et al. A phase II and pharmacological study of weekly oral paclitaxel (Paxoral®) plus cyclosporin A (CsA) in patients with advanced nonsmall cell lung cancer (NSCLC). J Clin Oncol 2002; 20: 4508-4516.61. Wozniak AJ. Single agent vinorelbine in the treatment of non-small cell lung cancer. Semin Oncol 1999; 26(suppl 16): 62-66.62. Lt Bokkel Huinink WW, Bergman B, Chemaissaini A and others. Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based therapy in locally advanced or metastatic non-small cell lung cancer. Lung Cancer 1999; 26: 85-94.63. Socinski MA. Single-agent paclitaxel in the treatment of advanced non-small cell lung cancer. The Oncologist 1999; 4: 408-416.64. Miller V, Kris M. Docetaxel (Taxotere) as a single agent and in combination chemotherapy for the treatment of patients with advanced non-small cell lung cancer. Semin Oncol 2000; 27(suppl 3): 3-10.65. Ranson M, Davidson N, Nicolson M, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small cell lung cancer. J Natl Cancer Inst 2000; 92: 1074-1080.66. Gatzemeier U, Heckmayr M, Neuhauss R, et al. Phase II study with paclitaxel for the treatment of advanced inoperable non-small cell lung cancer. Lung Cancer 1995; 12(suppl 2): S101- S106.67. Cullinan SA, Moertel CG, Wieand HS and others. Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. J Clin Oncol 1994; 12: 412-416.68. Wils JA, Klein HO, Wagener DJ and others. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin. A step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 1991; 9:827831.69. Webb A, Cunningham D, Scarffe H, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997; 15: 261-267.70. Boot H, Cats A, Tonino S and others. Epirubicin, cisplatin and continuous 5-FU chemotherapy (ECF-regimen) in patients with cancer of the gastroesophageal junction and stomach. Gastroenterology 2002; 122(suppl): A601.71. Ohtsu A, Boku N, Tamura F and others. An early phase II study of a 3-hour infusion of paclitaxel for advanced gastric cancer. Am J Clin Oncol 1998; 21: 416-419.72. Cascinu S, Graziano F, Cardarelli N et al. Phase II study of paclitaxel in pretreated advanced gastric cancer. Anticancer Drugs 1998; 9: 307-310.73. Einzig AL, Lipsitz S, Wiernik PH, et al. Phase II trial of Taxol in patients with adenocarcinoma of upper gastrointestinal tract (UGIT). The Eastern Cooperative Oncology Group (ECOG) results. Invest New Drugs 1995; 3: 223-227.74. Huizing MT, Keung AC, Rosing H et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum pretreated ovarian cancer patients. J Clin Oncol 1993; 11: 2127-2135.75. Malingré MM, Richel DJ, Beijnen JH and others. Coadministration of cyclosporin A strongly enhances the oral bioavailability of docetaxel. J Clin Oncol 2001; 19: 1160-1166.76. Burstein HJ, Manola J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18: 1212-1219.77. Kruijtzer CMF, Malingré MM, Schornagel JH et al. A phase II study with weekly oral docetaxel and cyclosporin A in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 2001; 20: 1941.78. Luck HJ, Donnè S, Glaubitz M et al. Phase I study of weekly docetaxel (Taxotere®) in heavily pretreated breast cancer patients. Eur J Cancer 1997; 33(suppl): 158.79. Hainsworth JD, Burris 3rd HA, Yardley DA, et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network Phase II trial. J Clin Oncol 2001; 19: 3500-3505.80. Bruno R, Hille D, Riva A and others. Population pharmacokinetics/ pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 1998; 16: 187-196.81. Rosing H, Lustig V, van Warmerdam LJ, et al. Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion. Cancer Chemother Pharmacol 2000; 45:213218.82. Myers BD, Ross J, Newton L, et al. Cyclosporine- associated chronic nephropathy. N Engl J Med 1984; 311: 699-705.83. Mastalerz H, Cook D, Fairchild CR, Hansel S, Johnson W, Kadow JF, Long BH, Rose WC, Tarrant J, Wu MJ, Xue MQ, Zhang G, Zoeckler M, Vyas DM. The discovery of BMS-275183: an orally effective novel taxane. Bioorg Med Chem. 2003; 11: 4315-23.84. J. Collett, C. Moreton. Modified-release peroral dosage forms. In: M. E. Aulton, editor. Pharmaceutics: the science of dosage form design, 2nd edition, London: Churchill Livingstone, 2002: 289-305.85. R. Bruno and G. J. Sanderink, Pharmacokinetics and metabolism of Taxotere (docetaxel). Cancer Surv 17, 305-313 (1993).86. W. J. Loos, S. D. Baker, J. Verweij, J. G. Boonstra and A. Sparreboom, Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins. Clin Pharmacol Ther 74, 364371 (2003).87. B. S. Kappelhoff, A. D. R. Huitema, K. M. L. Crommentuyn, J. W. Mulder, P. L. Meenhorst, E. C. van Gorp, A. T. Mairuhu and J. H. Beijnen, Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients. Br J Clin Pharmacol 59, 174-182(2005).88. Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. December 2006; 2(6): 875-9489. Xie W, Evans RM. Pharmaceutical use of mouse models humanized for the xenobiotic receptor. Drug Discov Today. May 1, 2002; 7(9): 509-15.90. Iyer M, Reschly EJ, Krasowski MD. Functional evolution of the pregnane X receptor. Expert Opin Drug Metab Toxicol. June 2006; 2(3): 381-97.91. Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolizing enzymes. Clin Pharmacokinet. 2003; 42(15): 1331-57.92. Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics. January 2004; 14(1): 1-18.93. Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 1999; 88(10): 1058 1066.94. Karanth H, Shenoy VS, Murthy RR. Industrially feasible alternative approaches in the manufacture of solid dispersions: a technical report. AAPS PharmSciTech 2006; 7(4): 87.95. Chen J, Qiu L, Hu M, Jin Y, Han J. Preparation, characterization and in vitro evaluation of solid dispersions containing docetaxel. Drug Development and Industrial Pharmacy 2008; 34:588-594.96. Schellekens RC, Stuurman FE, van der Weert FH, Kosterink JG, Frijlink HW. A novel dissolution method relevant to intestinal release behavior and its application in the evaluation of modified release mesalazine products. Eur. J. Pharm. Sci. 2007 Jan; 30(1): 15-20.97. Dressman JB, Reppas C. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur. J. Pharm. Sci. October 2000; 11: S73-S80.98. The Handbook of Pharmaceutical Excipients. Fifth Edition. Edited by Raymond Rowe, Paul Sheskey and Sian Owen. See section on Povidone.99. Kruijtzer CM, Boot H, Beijnen JH et al. Weekly oral paclitaxel as first line treatment in patients with advanced gastric cancer. Ann Oncol 2003; 14: 197-204,100. Helgason H, Kruijtzer CM, Huitema ADR, et al. Phase II and pharmacological study of oral paclitaxel (Paxoral) plus cyclosporin in anthracycline-pretreated metastatic breast cancer. Brit J Cancer 2006; 95:794-800,101. Kuppens IE, Van Maanen MJ, Rosing H, Schellens JHM, Beijnen JH. Quantitative analysis of docetaxel in human plasma using liquid chromatography coupled with tandem mass spectrometry. Biomed Chromatogr 2005; 19: 355-361.

Claims (6)

1. Solid pharmaceutical composition for oral administration, characterized by the fact that it comprises an amorphous taxane, a hydrophilic vehicle and a surfactant, in which the taxane, the vehicle and the surfactant are in the form of a solid dispersion, in which the weight ratio of taxane to vehicle is between 2.5:97.5 w/w and 1:9 w/w, in which the weight ratio of the surfactant to taxane and vehicle combined is between 2:98 w/w and 17:83 w/w, in which the vehicle is PVP-K30, and in which the surfactant is sodium dodecyl sulfate. 2. Composition according to claim 1, characterized in that the ratio between the taxane and the vehicle is between 5:95 w/w and 1:9 w/w. 3. Composition according to claims 1 or 2, characterized in that the taxane/vehicle weight ratio is 1:9 w/w. 4. Composition according to any one of claims 1 to 3, characterized in that the taxane is docetaxel. 5. Use of the composition as defined in any one of claims 1 to 4, characterized in that it is in the preparation of a medicament for the treatment of a solid tumor. 6. A method for preparing a composition as defined in any one of claims 1 to 4, comprising the steps of: dissolving a taxane, a hydrophilic carrier, and a surfactant in a solvent, wherein the weight ratio of taxane to carrier is between 2.5:97.5 w/w and 1:9 w/w, the weight ratio of the surfactant to taxane and carrier combined is between 2:98 w/w and 17:83 w/w, the carrier is PVP-K30, and the surfactant is sodium dodecyl sulfate; and subjecting the solution to lyophilization or a solvent evaporation method to form the composition.