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GB2372444A - A pharmaceutical formulation comprising bicalutamide and a hydroxypropylmethylcellulose polymer - Google Patents

A pharmaceutical formulation comprising bicalutamide and a hydroxypropylmethylcellulose polymer Download PDF

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Publication number
GB2372444A
GB2372444A GB0104749A GB0104749A GB2372444A GB 2372444 A GB2372444 A GB 2372444A GB 0104749 A GB0104749 A GB 0104749A GB 0104749 A GB0104749 A GB 0104749A GB 2372444 A GB2372444 A GB 2372444A
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Prior art keywords
bicalutamide
solid dispersion
polymer
formulation
patient
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GB0104749A
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GB0104749D0 (en
Inventor
Julie Cahill
William Edward Fieles
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AstraZeneca AB
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AstraZeneca AB
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Priority to GB0104749A priority Critical patent/GB2372444A/en
Publication of GB0104749D0 publication Critical patent/GB0104749D0/en
Priority to NZ527532A priority patent/NZ527532A/en
Priority to SK1072-2003A priority patent/SK10722003A3/en
Priority to KR10-2003-7011178A priority patent/KR20030077042A/en
Priority to RU2003128971/15A priority patent/RU2003128971A/en
Priority to DE60206889T priority patent/DE60206889T2/en
Priority to CA002439366A priority patent/CA2439366A1/en
Priority to PL02365746A priority patent/PL365746A1/en
Priority to EP02712105A priority patent/EP1368001B1/en
Priority to PCT/GB2002/000766 priority patent/WO2002067893A2/en
Priority to MXPA03007641A priority patent/MXPA03007641A/en
Priority to JP2002567261A priority patent/JP3548566B2/en
Priority to AT02712105T priority patent/ATE307571T1/en
Priority to EEP200300416A priority patent/EE200300416A/en
Priority to IL15738902A priority patent/IL157389A0/en
Priority to CZ20032225A priority patent/CZ20032225A3/en
Priority to HU0302847A priority patent/HUP0302847A3/en
Priority to CNA028087356A priority patent/CN1503662A/en
Priority to US10/468,276 priority patent/US20040067257A1/en
Priority to UY27186A priority patent/UY27186A1/en
Priority to ARP020100712A priority patent/AR032912A1/en
Publication of GB2372444A publication Critical patent/GB2372444A/en
Priority to IS6915A priority patent/IS6915A/en
Priority to ZA200306383A priority patent/ZA200306383B/en
Priority to NO20033785A priority patent/NO20033785L/en
Priority to JP2004041583A priority patent/JP2004143185A/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical formulation for mucosal adminstration comprising bicalutamide in a solid dispersion with a hydroxypropylmethylcellulose phthalate (HPMCP) polymer. The invention also relates to a daily pharmaceutical dose of bicalutamide provided by such a formulation. In addition, the invention relates to the use of a HPMCP polymer in solid dispersion with bicalutamide for increasing the bioavailability of the bicalutamide; for reducing inter-patient variability in plasma concentrations of bicalutamide; or for treating and/or reducing the risk of prostate cancer in a patient.

Description

PHARMACEUTICAL FORMULATION
The present invention relates to a pharmaceutical formulation comprising bicalutamide in a solid dispersion with a hydroxypropylmethylcellulose phthalate (HPMCP) polymer. The invention also relates to a daily pharmaceutical dose of bicalutamide provided by such a formulation. In addition, the invention relates to the use of a HPMCP polymer in solid dispersion with bicalutamide for increasing the bioavailability of the bicalutamide; for reducing inter-patient variability in plasma concentrations of bicalutamide ; or for treating and/or reducing the risk of prostate cancer in a patient.
BACKGROUND TO THE INVENTION Bicalutamide, a non-steroidal anti-androgen, is the racemate of 4'-cyano-a\a', o/- trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and is
TM known by the AstraZeneca trade name CASODEX. EP-100172 discloses 4'-cyanoa', a', a'-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide (named in EP-100172 as 4-cyano-3-trifluoromethyl-N- (3-p-fluorophenylsulphonyl-2hydroxy-2-methylpropionyl) aniline) as the 8h compound listed in the table in Example 6.
The corresponding structure is shown in formula I :
Bicalutamide can be used to combat prostate cancer. The properties and usefulness of bicalutamide as an anti-androgen have been reviewed in B J A Furr et al., Urology, 1996, 47 (Suppl. 1A), 13-25, and G J C Kolvenbag et al., Urology, 1996,47 (Suppl. 1A), 70-79.
Bicalutamide is used in conventional oral tablet form (eg, at a daily monotherapy dose of 150mg) to combat prostate cancer in men. The bioavailability of the bicalutamide to the patient is determined to a certain extent by the dissolution rate and solubility of the drug in the GI tract, which affects absorption across mucosal membranes in the GI tract. The relative bioavailability of bicalutamide for a series of formulations can be assessed by determining the area under the curve (AUC) of a graph of plasma bicalutamide concentration v. time elapsed since administration of the bicalutamide. As a consequence of sub-optimal rates of dissolution and degree of solubility of the drug, there is observed a high degree of inter-patient variability in the bioavailability of bicalutamide administered in conventional tablet form. This may result in sub-optimal treatment efficacy in a proportion of patients. In addition, the maximum systemic exposure achievable after dosing the conventional tablet is limited, such that at conventional tablet doses in excess of 150mg, there is a significant reduction in bicalutamide bioavailability. At conventional tablet doses above 300mg, no further increase in systemic exposure is achievable It would be desirable to extend the therapeutic potential of bicalutamide by increasing the bioavailability of the drug and/or reducing inter-patient variability in plasma
concentrations of bicalutamide as a result of reduced inter-patient variability in the absorption of bicalutamide.
Such increased bioavailability could be useful in enabling a reduction in the daily dose of bicalutamide required to achieve the same level of bioavailability seen with a conventional formulation.
A possible benefit of achieving relatively higher bioavailability could also be the ability to extend treatment to more advanced stages of prostate cancer than are currently treated with
the conventional formulations. This could be useful, for example, for treating patients with metastatic prostate cancer, using for example bicalutamide as a monotherapy (ie, not in combination with LHRH analogue therapy or surgical castration).
As another advantage, it would also be desirable to reduce inter-patient variability in plasma concentrations of bicalutamide as a result of reduced inter-patient variability in the absorption of bicalutamide. This would increase predictability of the treatment and increase uniformity of treatment in a patient population.
EP-0988863 deals with the issue of increasing the bioavailability of poorly soluble drugs in general. Bicalutamide is not specifically addressed. The disclosed solution is to provide a formulation comprising a water-insoluble complex of the drug and a water-insoluble ionic polymer. No specific class of polymer is required, and the polymer can be cationic or anionic, but must have a molecular weight greater than about 80,000 D and a glass transition temperature equal or greater than about 50oC.
EP-1027886 also deals with the issue of increasing the bioavailability of poorly soluble drugs in general. Again, bicalutamide is not specifically addressed. The disclosed solution is to provide a solid dispersion formulation comprising a low-solubility drug and a polymer. The latter can be one of many possible polymers, as long as it has a glass transition temperature of at least 100oC measured at 50% relative humidity. Certain grades TM TM
of HPMCP polymers are explicitly excluded from use. These include HP-50, HP-55 TM and HP-55S The present invention aims to improve upon the conventional formulation of bicalutamide by increasing the therapeutic potential of bicalutamide as discussed above.
SUMMARY OF THE INVENTION
The present invention fulfils this aim by providing a pharmaceutical formulation for mucosal administration to a patient, the formulation comprising bicalutamide in a solid dispersion with a HPMCP polymer.
The invention also provides a daily pharmaceutical dose ofbicalutamide mucósally administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 25 to 600mg of bicalutamide in a solid dispersion with a HPMCP polymer.
Further aspects of the invention relate to the use of a HPMCP polymer in solid dispersion with bicalutamide, in the manufacture of a medicament mucosally administrable to a patient, for (a) increasing the bioavailability of bicalutamide in the patient; or (b) treating and/or reducing the risk of prostate cancer in the patient. As explained below, reducing the risk of prostate cancer includes reducing the risk of re-occurrence of prostate cancer.
In addition, the invention relates to the use of a HPMCP polymer in solid dispersion with bicalutamide, in the manufacture of a medicament mucosally administrable to patients, for reducing inter-patient variability in plasma concentrations of bicalutamide.
FIGURES Fig. 1 Dissolution of bicalutamide from various solid dispersion formulations (50mg bicalutamide in 900ml of media).
Key : Diamonds-conventional bicalutamide tablet formulation Triangles-PEG4000 Rectangles-PLA : PEG [2K : 2K] Crosses-HP-55S Fig. 2 Dissolution ofbicalutami'de from solid dispersion formulations (50mg bicalutamide in 900ml of media) comprising bicalutamide with HP-55S at various weight ratios.
Key : The following ratios relate to weight ratios of bicalutamide : HP-55S Diamonds-1 : 5 Squares-1 : 4 Triangles-1 : 3 Crosses-1 : 2 Circles-1 : 1 Broken line-conventional bicalutamide tablet formulation.
Fig. 3 Plasma profiles following administration of bicalutamide formulations to dogs (n=6,450mg bicalutamide dose). The vertical bars indicate variability.
Key :- Solid line-solid dispersion of 1 : 3 by weight of bicalutamide : HP-55S Broken line-conventional bicalutamide tablet formulation.
DETAILED DESCRIPTION OF THE INVENTION
The inventors chose to investigate solid dispersion formulations as a possible means of increasing the therapeutic potential of bicalutamide. The aim was to increase the therapeutic potential by achieving one or both of an in increase the bioavailability of bicalutamide and a decrease in inter-patient variability in plasma concentrations of bicalutamide.
The prior art teaches a very wide range of possible polymers for solid dispersion, in order to increase the bioavailability of drugs in general. The inventors have now surprisingly found that the therapeutic potential of bicalutamide can be increased by formulating bicalutamide in a solid dispersion specifically with a HPMCP polymer. As the nonlimiting example section below demonstrates, such an increase in therapeutic potential for bicalutamide is not achieved with other polymers.
The use of the term"hydroxypropylmethylcellulose phthalate polymer", or HPMCP polymer, is known to the skilled reader for classifying a group of polymers which share the same basic structural features and include such polymers as : hypromellose phthalate ; methylhydroxypropylcellulosi pthalas; cellulose, hydrogen l, 2-benzenedicarboxylate, 2 TM TM
hydroxypropyl methyl ; as well as commercially available polymers HP-55, HP-55S TM and lIP-50 (available from Shin-Etsu Chemical Industry Co., Ltd., Japan or appointed distributors).
Preferably the hydroxypropylmethylcellulose phthalate polymer has a molecular weight (Mw) from 20kDa to 200kDa, eg from 80kDa to 130kDa. In one embodiment, the Mw is less than 150kDa, or less than 100ka. HP-50, lIP-55 and HP-55S are polymers known m the literature and widely used as an enteric coating for oral formulations. HP-55 has a Mw 84kDa. HP-55S has a Mw of 132kDa. HP-50 has a Mw 78kDa.
Preferably, the bicalutamide is in a solid dispersion with at least one polymer selected from HP-50, HP-55 and HP-55S. Thus, it is contemplated that a mixture of two or more of these HPMCP polymers can be used.
A preferred ratio of bicalutamide : HPMCP polymer by weight is from 1: 0.25 to 1 : 10.
More preferably the lower limit of this range is 1: 0.5, 1: 0.75 or 1: 1. Preferably, the upper limit of this range is 1 : 3 or 1: 5. A most preferred range of ratios is 1: 1 to 1 : 3.
One aspect of the invention provides a daily pharmaceutical dose of bicalutamide mucosally administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 25 to 600mg of bicalutamide in a solid dispersion with a HPMCP polymer. Preferably, the dose comprises an upper limit of 500, 450,400, 300,200, 150,125, 100,75 or 50mg of bicalutamide. In one example, the dose comprises 450mg of bicalutamide.
Additional excipients may be included in the formulation or dose. For example, the formulation or dose may comprise one or more fillers, binder, disintegrants and/or lubricants.
Suitable fillers include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e. g. microcrystalline cellulose, cellulose), calcium sulfate, xylitol and lactitol.
Suitable binders include, for example, polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate.
Suitable disintegrants include, for example, crosscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, camuba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate.
Additional conventional excipients which may be added include preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents or glidants.
Other suitable fillers, binders, disintegrants, lubricants and additional excipients which may be used are described in the Handbook of Pharmaceutical Excipients, 3rd Edition ; The Theory and Practice of Industrial Pharmacy, 3rd Edition 1986 ; Pharmaceutical Dosage Forms 1998 ; Modem Pharmaceutics, 3rd Edition 1995 ; Remington's Pharmaceutical Sciences 20th Edition 2000.
Preferably, the bicalutamide will be present in an amount of 1 to 80%, and preferably from 1 to 50% (more preferably 2 to 20% or 2 to 15%) by weight of the formulation.
Preferably, one or more fillers will be present in an amount of 1 to 70% by weight.
Preferably, one or more binders will be present in an amount of 2 to 40% by weight.
Preferably, one or more disintegrants will be present in an amount of 1 to 10%, and especially 4 to 6% by weight.
It will be appreciated that a particular excipient may act as both a binder and a filler, or as a binder, a filler and a disintegrant. Typically the combined amount of filler, binder and disintegrant comprises, for example, I to 90% by weight of the formulation.
Preferably, one or more lubricants will be present in an amount of 0. 5 to 3%, and especially I to 2% by weight.
Methods for preparing solid dispersions are known in the art and typically comprise the steps of dissolving the drug and the polymer in a common solvent and evaporating the solvent. The solvent can be routinely selected according to the polymer used. Examples of solvents are: acetone/dichloromethane, methanol/dichloromethane, acetone/water, acetone/ethanol, dichloromethane/ethanol or ethanol/water. For HP-50, for example, the last four solvents can be used. Methods for evaporating solvent include rotary evaporation, spray drying, lyophilisation and thin film evaporation. Other techniques may be used such as solvent controlled precipitation, pH controlled precipitation, supercritical fluid technology and hot melt extrusion (to aid the process the melt may be extruded with any necessary additional excipient, such as a plasticiser).
When referring to a solid dispersion we do not exclude the possibility that a proportion of the bicalutamide may be dissolved within the polymer used, the exact proportion, if any, will depend upon the particular HPMCP polymer selected.
In the formulations of the invention, at least some of the bicalutamide may be present in amorphous form in the solid dispersion with the HPMCP polymer. The provision of the bicalutamide in amorphous form is additionally advantageous, since it further increases the solubility and dissolution rate of the bicalutamide, thereby enhancing the increase in therapeutic potential achieved with the present invention. Whether or not drug is present in amorphous form can be determined by conventional thermal analysis. In one embodiment, at least 25% of the bicalutamide in the formulation is present in amorphous form. More preferably, this amount is at least 30%, 40%, 50%, 75%, 90%, 95% or 99%.
The most preferred embodiment is where 100% of the bicalutamide in the formulation is in amorphous form.
The formulations and doses are mucosally administrable, ie administrable to mucosal membranes for absorption across the membranes. To this end, suitable routes of
administration include administration by inhalation, as well as oral, intranasal and rectal administration. Oral administration is particularly preferred. A tablet or other form of the formulation would be chosen by the skilled addressee according to the route of administration.
The bicalutamide is useful to provide an anti-androgenic effect, in that this compound blocks androgen activity in a patient. The anti-androgenic effect is useful for treating cancer, for example prostate cancer. Particular examples are advanced prostate cancer and early prostate cancer. The anti-androgenic effect may be useful for prophylaxis, in order to reduce the risk of prostate cancer occurrence in patients or re-occurrence (eg, following prostatectomy or radiation therapy aimed at curing the patient). This could be especially useful in men genetically pre-disposed to prostate cancer. Conventional methods are available to classify patients according to their risk of contracting prostate cancer, for example by assessment of family history and measurements over time of particular blood proteins such as prostate specific antigen (PSA). Other uses for the anti-androgenic effect are the treatment of a non-malignant disease of the prostate gland (eg, benign prostatic hyperplasia or hypertrophy) and acne.
The patient can be a human male, eg an adult, but the treatment of other mammals is also contemplated.
EXPERIMENTAL In Vitro Assessment of Various Solid Dispersion Formulations The inventors formulated a solid dispersion of bicalutamide with a representative HPMCP polymer (in this case HP-55S) and compared this against solid dispersions using several different polymers with bicalutamide. A conventional tablet bicalutamide formulation was also included for comparison. The formulations were assessed for an improvement in therapeutic potential using an in vitro dissolution test.
Each formulation had a weight ratio of bicalutamide : polymer of 1 : 5. The following polymers were used to produce solid dispersions : - polyethylene glycol (PEG) 4000, PLA : PEG [2K : 2K] (a di-block copolymer of poly (lactide) : polyethylene glycol) and HP55S.
The performance of solid dispersions having varying weight ratios ofbicalutamide : HP-55S was also assessed.
Preparation of Solid Dispersion Formulations Solid dispersions having a 1 : 5 ratio by weight of bicalutamide : polymer were prepared as follows.
0. 5g ofbicalutamide and 2. 5g of polymer were weighed directly into a 250ml round bottom flask and dissolved in 80ml of acetone : dichloromethane (3: 1). The solvent was removed on a rotary evaporator. The formulation was placed in a vacuum oven and dried under high vacuum at 40oC for 24 hours.
The formulation was retrieved from the flask and dry milled using a Fritsch mill. The formulation was then dried for a further 24 hours under high vacuum at 40oC.
In order to produce formulations having ratios other than 1: 5, weights and volumes in the process should be adjusted so that they are pro-rata to those described above.
for one hour at 37 C (paddle speed 75rpm). 5ml samples were then removed with a plastic syringe at 5, 10, 20, 30, 45 and 60 minutes. Each sample was centrifuged (14, 000rpm) at ambient temperature for 15 minutes and then analysed by HPLC using the following conditions : Eluent: 58% ACN/42% water/0.2% formic acid Column :'15cm Luna 5um, 3mm id column (with'guard) Detection wavelength: 270nm Flow rate: 1 ml/min Temperature: ambient Injection: 1 Oul Retention time: approximately 2 minutes Figure I shows the results of in vitro dissolution tests performed on the various solid dispersions. As Fig. l shows, 100% of bicalutamide in solution was achieved with the HP55S solid dispersion and supersaturation was maintained over the 60 minute test (ie, no drug precipitation was observed). Compare this against the results for the PLA: PEG solid dispersion, which did not show any improvement over the conventional tablet formulation.
The PEG4000 solid dispersion also was much inferior to the HP-55S formulation, the former achieving only approximately 50% of bicalutamide in solution.
(b) Solid Dispersions With Varying Ratios of Bicalutamide : HP-55S Solid dispersions were made with weight ratios of 1 : 1, 1 : 2, 1 : 3, 1 : 4 and 1 : 5 bicalutamide : HP-55S. These were tested in the in vitro dissolution test, and the results are presented in Fig. 2. A conventional bicalutamide tablet formulation was included for comparison.
As Fig. 2 shows, for all of the formulations comprising HP-55S, 100% ofbicalutamide in solution was achieved and supersaturation was maintained over the 60 minute test. These results were superior to the results achieved with the conventional formulation.
In Vivo Evaluation Oral doses of bicalutamide were administered to fasted dogs (equivalent to 450mg TM drug) (n=6). The formulations dosed were conventional CASODEX tablets and a 1 : 3 [bicalutamide : HP55S] solid dispersion. The solid dispersion was prepared as described earlier, however the solvent was removed by spray drying as opposed to rotary evaporation. Each oral dose was followed by 20ml of water. Blood samples were taken pre-dose and post dose at 1,2, 3,4, 6,8, 12,18, 24,30, 36,48, 72,96, 120,144, 168 hours.
The samples centrifuged at 3000rpm for 15 minutes, the plasma removed into plain blood tubes and stored at -20OC until analysis. Samples were analysed by using a suitable extraction method followed by LC-MS. Summary of Pharmacokinetic Parameters
FORMULATION Cpmax ( g/ml) Tmax (hours) AUC ( g/h/ml)* HP-55S solid dispersion 13 30 1504 ~ 309 Conventional formulation 5 30 500 : ! : 405 * AUC & om 0 to 168 hours These data, as well as Fig. 3, show that the bioavailability ofbicalutamide is greater with the solid dispersion. In fact, the AUC measurements show a figure for the HP-55S solid dispersion that is almost 3 times that of the conventional tablet formulation. In addition, Cmax for the HP-55S solid dispersion is almost 3 times that of the conventional tablet formulation. Furthermore, inter-subject variability in the plasma levels of bicalutamide is lower with the HP-55S solid dispersion than with the conventional tablet formulation (for variability/total AUC, compare a figure of 309/1504 g/h/ml for theHP-55S solid dispersion against a figure of 405/500 u. g/h/ml for the conventional tablet formulation).

Claims (16)

CLAIMS :
1. A pharmaceutical formulation for mucosal administration to a patient, the formulation comprising bicalutamide in a solid dispersion with a hydroxypropylmethylcellulose phthalate (HPMCP) polymer.
2. The formulation of claim 1, wherein the bicalutamide is in a solid dispersion with at least one polymer selected from HP-50, HP-55 and HP-55S.
3. The formulation of claim 2, wherein the bicalutamide is in solid dispersion with HP 55S.
11
4. The formulation of any preceding claim, wherein the ratio of bicalutamide : HPMCP polymer by weight is from 1 : 0.75 to 1: 10.
5. A daily pharmaceutical dose of bicalutamide mucosally administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose
comprises 25 to 600mg of bicalutamide in a solid dispersion with a HPMCP polymer.
6. The daily dose of claim 5, wherein the bicalutamide is in a solid dispersion with at least one polymer selected from HP-50, HP-55 and HP-55S.
7. The daily dose of claim 6, wherein the bicalutamide is in solid dispersion with HP-55S.
8. The daily dose of any one of claims 5 to 7, wherein the ratio of bicalutamide : HPMCP polymer by weight is from 1 : 0.75 to 1 : 10.
9. A solid dispersion of a HPMCP polymer with bicalutamide for use as a medicament.
10. Use of a HPMCP polymer in solid dispersion with bicalutamide, in the manufacture of a medicament mucosally administrable to a patient, for increasing the bioavailability of bicalutamide in the patient.
11. Use of a HPMCP polymer in solid dispersion with bicalutamide, in the manufacture of a medicament mucosally administrable to patients, for reducing inter-patient variability
in plasma concentrations of bicalutamide.
12. Use of a HPMCP polymer in solid dispersion with bicalutamide, in the manufacture of a medicament mucosally administrable to a patient, for treating and/or reducing the risk of prostate cancer in the patient.
13. The use according to claim 12, wherein the medicament is provided as a daily dose of bicalutamide and comprises 25 to 600mg of bicalutamide.
14. The use according to any one of claims 10 to 13, wherein the bicalutamide is in a solid dispersion with at least one polymer selected from HP-50, HP-55 and HP-55S.
15. The use according to claim 14, wherein the bicalutamide is in solid dispersion with HP 55S.
16. The use according to any one of claims 10 to 15, wherein the ratio of bicalutamide in the medicament: HPMCP polymer by weight is from 1 : 0.75 to 1 : 10.
GB0104749A 2001-02-27 2001-02-27 A pharmaceutical formulation comprising bicalutamide and a hydroxypropylmethylcellulose polymer Withdrawn GB2372444A (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
GB0104749A GB2372444A (en) 2001-02-27 2001-02-27 A pharmaceutical formulation comprising bicalutamide and a hydroxypropylmethylcellulose polymer
US10/468,276 US20040067257A1 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation
AT02712105T ATE307571T1 (en) 2001-02-27 2002-02-22 PHARMACEUTICAL FORMULATION CONTAINING BICALUTAMID
IL15738902A IL157389A0 (en) 2001-02-27 2002-02-22 A pharmaceutical formulation comprising bicalutamide and an enteric polymer and use thereof as a medicament
KR10-2003-7011178A KR20030077042A (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
RU2003128971/15A RU2003128971A (en) 2001-02-27 2002-02-22 PHARMACEUTICAL PRODUCT
DE60206889T DE60206889T2 (en) 2001-02-27 2002-02-22 PHARMACEUTICAL FORMULATION CONTAINING BICALUTAMIDE
CA002439366A CA2439366A1 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
PL02365746A PL365746A1 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
EP02712105A EP1368001B1 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
PCT/GB2002/000766 WO2002067893A2 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
MXPA03007641A MXPA03007641A (en) 2001-02-27 2002-02-22 Pharmaceutical formulation.
JP2002567261A JP3548566B2 (en) 2001-02-27 2002-02-22 Pharmaceutical preparations
NZ527532A NZ527532A (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
EEP200300416A EE200300416A (en) 2001-02-27 2002-02-22 Pharmaceutical form
SK1072-2003A SK10722003A3 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide in solid dispersion with an enteric polymer and use thereof
CZ20032225A CZ20032225A3 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation
HU0302847A HUP0302847A3 (en) 2001-02-27 2002-02-22 Pharmaceutical formulation comprising bicalutamide
CNA028087356A CN1503662A (en) 2001-02-27 2002-02-22 pharmaceutical preparations
UY27186A UY27186A1 (en) 2001-02-27 2002-02-26 PHARMACEUTICAL FORMULATION
ARP020100712A AR032912A1 (en) 2001-02-27 2002-02-27 PHARMACEUTICAL FORMULATION
IS6915A IS6915A (en) 2001-02-27 2003-08-15 composition
ZA200306383A ZA200306383B (en) 2001-02-27 2003-08-15 Pharmaceutical formulation comprising bicalutamide.
NO20033785A NO20033785L (en) 2001-02-27 2003-08-26 Pharmaceutical formulation
JP2004041583A JP2004143185A (en) 2001-02-27 2004-02-18 Pharmaceutical formulation

Applications Claiming Priority (1)

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GB0104749A GB2372444A (en) 2001-02-27 2001-02-27 A pharmaceutical formulation comprising bicalutamide and a hydroxypropylmethylcellulose polymer

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GB0104749D0 GB0104749D0 (en) 2001-04-18
GB2372444A true GB2372444A (en) 2002-08-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE202006000585U1 (en) * 2006-01-13 2007-05-24 Wanzl Metallwarenfabrik Gmbh Dividing means
EP1765346A4 (en) * 2004-01-28 2008-10-15 Androscience Corp STRENGTHENING ANTI-ANDROGEN ACTIVITY BY COMBINING INHIBITORS TARGETING DIFFERENT STEROID DEPENDENCE GENE ACTIVATION PATH PATTERNS, AND USES THEREOF

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029305A1 (en) * 1997-12-05 1999-06-17 Duramed Pharmaceuticals, Inc. Sustained release formulation containing three different types of polymers and tablet formed therefrom
WO2000015766A1 (en) * 1998-09-16 2000-03-23 Oncopharmaceutical, Inc. Treatment of oncologic tumors with an injectable formulation of a golgi apparatus disturbing agent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029305A1 (en) * 1997-12-05 1999-06-17 Duramed Pharmaceuticals, Inc. Sustained release formulation containing three different types of polymers and tablet formed therefrom
WO2000015766A1 (en) * 1998-09-16 2000-03-23 Oncopharmaceutical, Inc. Treatment of oncologic tumors with an injectable formulation of a golgi apparatus disturbing agent

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1765346A4 (en) * 2004-01-28 2008-10-15 Androscience Corp STRENGTHENING ANTI-ANDROGEN ACTIVITY BY COMBINING INHIBITORS TARGETING DIFFERENT STEROID DEPENDENCE GENE ACTIVATION PATH PATTERNS, AND USES THEREOF
DE202006000585U1 (en) * 2006-01-13 2007-05-24 Wanzl Metallwarenfabrik Gmbh Dividing means

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GB0104749D0 (en) 2001-04-18
ZA200306383B (en) 2004-11-15

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