HK1161089B - Solid dosage forms of bendamustine - Google Patents

Abstract

In the present invention there is provided a pharmaceutical composition in a solid dosage form suitable for oral administration, the composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, which is a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1 :1-5.

Description

Solid dosage forms of bendamustine

Technical Field

The present invention relates to orally administered solid dosage forms comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof.

Background

Bendamustine (4- [5- [ bis (2-chloroethyl) amino ] -1-methylbenzimidazol-2-yl ] butanoic acid, a nitrogen mustard) is an alkylating agent with bifunctional alkylating activity. Which corresponds to the following structural formula I:

bendamustine appears to be free of any cross-resistance to other alkylating agents, which has advantages in chemotherapy for patients who have already been treated with alkylating agents.

Bendamustine was originally synthesized in the german democratic republic of morale (GDR). In 1971 to 1992 under the name CytostasanBendamustine hydrochloride is an active ingredient in commercial products sold. Since then, bendamustine hydrochloride was sold under the trade name Ribomustin in GermanySold and widely used for the treatment of chronic lymphoid disordersLeukemia, non-hodgkin's lymphoma, and multiple myeloma.

The commercial product comprises bendamustine hydrochloride lyophilized powder which is reconstituted with water for injection to produce a concentrate. This was then diluted with 0.9% aqueous sodium chloride to give the final solution for infusion. The final solution is administered to the patient by intravenous infusion over a period of about 30 to 60 minutes.

Hydrolysis of the di-2-chloroethylamino group of bendamustine in water results in decreased potency and the formation of impurities (B.Maas et al (1994), Pharmazie 49: 775-777). It must therefore be administered immediately after reconstitution of the lyophilized powder (usually in a hospital or at least under medical supervision). Furthermore, it has been reported that the reconstitution process is difficult. This process may take more than 30 minutes. In addition, reconstitution in a 2-step process is cumbersome and time consuming for medical professionals responsible for reconstituting products.

Preiss et al (1985) (Pharmazie 40: 782-784) compared the pharmacokinetics of bendamustine hydrochloride in the plasma of 7 patients following intravenous and oral administration at doses of 4.2mg/kg to 5.5mg/kg, respectively. From the commercial product CytostasanThe prepared intravenous infusion was administered within 3 minutes, while an equivalent dose of the oral drug was administered in the form of a capsule containing 25mg bendamustine hydrochloride. The number of capsules administered to patients varies from 10 to 14. After oral administration, maximum plasma levels were detectable within 1 hour. The mean oral bioavailability was calculated to be 57% ranging from 25% to 94%, which showed large inter-individual variation.

Weber (1991) (Pharmazie 46 (8): 589-591) studied the bioavailability of bendamustine hydrochloride in B6D2F 1-mice and found incomplete absorption of the drug from the gastrointestinal tract, which resulted in a bioavailability of only about 40%.

Patent document US 2006/0128777 a1 describes a method of treating cancer which is generally characterized by anti-dead cells and a composition containing bendamustine. Among these compositions are oral solid dosage forms in the form of capsules, tablets, pills, powders or granules, in which the active compound can be mixed with at least one inert excipient (for example sucrose, lactose or starch). However, it does not exemplify a specific composition.

In view of the stability problems associated with commercially available intravenous formulations once reconstituted with water, and in order to improve patient compliance, there has long been a need for a stable oral dosage form containing bendamustine which is easy to administer to patients and which provides improved bioavailability and reduced variability over known oral dosage forms.

Summary of The Invention

The present inventors have conducted detailed studies in order to solve the above problems. They finally succeeded in obtaining the stable pharmaceutical composition of the present invention. These compositions are suitable for oral administration and comprise: bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as active ingredient, and at least one pharmaceutically acceptable excipient, said composition having improved dissolution behaviour.

Brief description of the drawings

Figure 1 shows the mean plasma concentration (tablet versus capsule) versus time curves obtained after administration of bendamustine hydrochloride to puppies in the form of prior art capsules and in the form of tablet formulations of examples 6 to 8 (tablets 1 to 3) and example 9 (formulation 3) (tablet 4). Figure 1 clearly shows that the tablet formulation provides a higher maximum concentration of bendamustine compared to the prior art capsules.

Figure 2 shows a flow chart of a wet granulation manufacturing run.

Detailed Description

The present invention relates to a pharmaceutical composition comprising: bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides and sugar alcohols. Preferably, the weight ratio between the active ingredient and the excipient is in the range of 1: 1 to 1: 5, preferably in the range of 1: 2 to 1: 5, more preferably a ratio selected from 1: 5 and 1: 2.

In one embodiment, the present invention relates to a solid dosage form pharmaceutical composition for oral administration, the composition comprising: bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient which is a pharmaceutically acceptable sugar selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a sugar alcohol, wherein the weight ratio of the active ingredient to the excipient is in the range of 1: 1.

In a further embodiment, the present invention relates to a pharmaceutical composition in solid dosage form suitable for oral administration, the composition comprising: bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as active ingredient, and at least one pharmaceutically acceptable excipient which is a pharmaceutically acceptable sugar selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a sugar alcohol, wherein the weight ratio of the active ingredient to the sugar excipient is in the range of 1: 2 to 1: 5, and the composition exhibits bendamustine dissolution behavior as follows: bendamustine dissolves at least 60% within 20 minutes, at least 70% within 40 minutes and at least 80% within 60 minutes as measured according to the european pharmacopoeia in 500ml of dissolution medium at pH 1.5 using a paddle apparatus rotating at 50 rpm.

Within the scope of the above embodiments, a further preferred embodiment is a pharmaceutical composition wherein the pharmaceutically acceptable sugar is selected from the group consisting of one or more of mono-, di-and oligosaccharides, wherein the weight ratio of the active ingredient to the sugar excipient is in the range of 1: 2 to 1: 5, and wherein the composition exhibits bendamustine dissolution behavior as follows: bendamustine dissolves at least 60% within 20 minutes, at least 70% within 40 minutes and at least 80% within 60 minutes as measured according to the european pharmacopoeia in 500ml of dissolution medium at pH 1.5 using a paddle apparatus rotating at 50 rpm.

The invention is based inter alia on the unexpected finding that: by introducing an amount of a pharmaceutically acceptable sugar into the pharmaceutical composition, a specific and desirable dissolution behavior can be achieved.

It has been found that particularly good behaviour in terms of stability, tabletting properties, dissolution and impurity formation is achieved if a pharmaceutically acceptable sugar selected from the group consisting of one or more of monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides and sugar alcohols, and preferably one or more of monosaccharides, disaccharides and oligosaccharides, is used as excipient in a pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as active ingredient. The above sugars allow the composition to exhibit the following bendamustine dissolution behavior: bendamustine dissolves at least 60% within 20 minutes, at least 70% within 40 minutes and at least 80% within 60 minutes as measured according to the european pharmacopoeia in 500ml of dissolution medium at pH 1.5 using a paddle apparatus rotating at 50 rpm.

Within the above scope of the present invention, any combination of one or more of monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides and sugar alcohols may be used.

the sugars in the compositions of the present invention are preferably anhydrous dextrose, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, anhydrous lactose, lactose monohydrate, maltitol, xylitol, sucrose 97% + maltodextrin 3%, β -cyclodextrin, D-pentaraffinose, D-melezitose monohydrate, and microcrystalline cellulose.

The sugars described above constitute preferred embodiments of the present invention, and any combination thereof may be used. Preferably, the ratio of the active ingredient to the above sugar is in the range of 1: 1 to 1: 5, preferably in the range of 1: 2 to 1: 5, and more preferably is selected from the group consisting of 1: 5 and 1: 2.

A further preferred embodiment of the present invention is a pharmaceutical composition in solid dosage form for oral administration comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as active ingredient and at least one pharmaceutically acceptable excipient selected from the group consisting of anhydrous dextrose, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, anhydrous lactose, lactose monohydrate, maltitol, xylitol, sucrose 97% + maltodextrin 3%, β -cyclodextrin, D-pentahydrated raffinose, D-melezitose monohydrate and microcrystalline cellulose, said composition exhibiting a dissolution of bendamustine of at least 60% within 10 minutes, a dissolution of at least 70% within 20 minutes and a dissolution of at least 80% within 30 minutes.

Particularly preferred sugars are mannitol, maltitol, erythritol, xylitol, lactose, sucrose, glucose (glucose), sorbitol, maltose, trehalose, lactitol and dextrose (dextrose) (anhydrous or monohydrate), and the weight ratio of the active ingredient to the sugar is preferably in the range of 1: 2 to 1: 5. The invention also includes combinations of two or more sugars within the scope of the above sugars.

The person skilled in the art is fully enabled to select suitable combinations among the above mentioned sugar excipients and to obtain compositions showing the following bendamustine dissolution behaviour: bendamustine is at least 60% dissolved in 20 minutes, at least 70% dissolved in 40 minutes and at least 80% dissolved in 60 minutes, measured according to the european pharmacopoeia in 500ml of dissolution medium at pH 1.5 using a paddle apparatus rotating at 50 rpm.

In a preferred embodiment, the composition is in the form of a tablet, granule, or pill.

The preferred dosage form is a tablet. The term tablet also includes fast disintegrating tablets, among which dispersible tablets and effervescent tablets.

The most common tablet preparation methods are direct compression, dry granulation and wet granulation. Direct compression involves compression molding a mixture containing The active ingredient and excipients on a tablet press (l.lachman et al, The Theory and practice of Industrial Pharmacy, third edition, 1986). In order to prepare tablets having a uniform content of active ingredient, the mixture to be compression-molded must have both good flowability and good compression moldability. It is not always possible to obtain good flowability by adding suitable excipients to the mixture, such as lubricants, anti-adherents and flow promoters. The mixture is often granulated before compression molding.

Granulation is a process in which a powdery mixture is formed into aggregates (called granules) having an approximately spherical or regular shape. This process can be achieved by dry granulation and wet granulation. Granulation is also used to convert powder mixtures with low cohesion into aggregates which when compression molded give tablets with good cohesive properties.

In the case of rapidly disintegrating tablets, the active ingredient, optionally mixed with one or more excipients, is advantageously provided with a coating to mask the taste of the active ingredient and/or to protect the active ingredient from possible harmful effects caused by light and/or moisture, and in the case of bendamustine, to protect the oral mucosa from harmful effects caused by the active compound. For this purpose, the granules are preferably prepared and processed as further described below.

The expression "particle" refers to an aggregate of particles, sometimes also referred to as a pellet. Granules are generally prepared by compaction and/or compression moulding techniques (dry granulation); or by wet granulation with a liquid in which a wet granulation binder is optionally dissolved (Remington's Pharmaceutical Sciences, 18 th edition, 1990, page 1641). Wet granulation techniques also include extrusion techniques. The term granulate therefore also includes pellets, prills, and extrudates, wherein a preferred example of a granulate is a pellet.

Pellets can be described as small granules having a certain density and a diameter of about 1.0 to 1.6mm, which are prepared by applying a pharmaceutical process of extrusion spheronization to a powdered mixture.

The active ingredient, optionally mixed with one or more excipients, may advantageously be provided with a coating to mask the taste of the active ingredient and/or to protect the active ingredient from possible harmful effects caused by light and/or moisture and/or to protect the oral mucosa from harmful effects caused by the active ingredient.

The pellets are small and round solid dosage forms prepared by adding the active ingredient to a soft triglyceride mixture. The mixture is rolled into a long strand, which is then cut into sections and rolled (J.T. Carstensen, Pharmaceutical principles of solid dowage forms, 1993, technical publishing company, page 63).

The dosage forms of the present invention are preferably prepared by dry compaction techniques. Suitable techniques are described, for example, in Pharmaceutical Sciences of Remington, 18 th edition, 1990, page 1644. They include dry granulation, rolling and direct compression. When tablets are prepared using these techniques, direct compression is more advantageous.

The dosage form according to the invention preferably has a coating. The coating has different purposes: can be used to mask the taste of the active ingredients used in the composition while protecting said active ingredients from possible harmful effects caused by light and/or moisture, such as oxidation, degradation, etc. In addition, the coating layer may protect the oral mucosa of the subject from damage caused by the active ingredient.

The coating layer may be applied to the dosage form by techniques well known in the art, such as spraying and microencapsulation. For tablets, they may be in the form of film coatings, sugar coatings or press coatings. Preferably, a film coating process is used (Pharmaceutical Sciences, 18 th edition, 1990, page 1666, Remington). In the case of rapidly disintegrating tablets coated as required by the active ingredient, the individual granules may be suitably coated before compression molding into tablets.

The expression "pharmaceutically acceptable ester thereof" refers to any pharmaceutically acceptable ester of bendamustine, such as the ester of bendamustine with an alkyl alcohol and the ester with a sugar alcohol. An example of an alkyl alcohol is C_1-6Alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol and tert-butanol. Examples of sugar alcohols are mannitol, maltitol, sorbitol, erythritol, ethylene glycol, glycerol, arabitol, xylitol and lactitol. Preferred examples of bendamustine esters are ethyl esters, isopropyl esters, mannitol esters, and sorbitol esters, most preferably bendamustine ethyl ester.

The expression "pharmaceutically acceptable salt thereof" refers to any pharmaceutically acceptable salt of bendamustine that is administered to a patient (directly or indirectly) to provide bendamustine. The term also includes pharmaceutically acceptable salts of bendamustine esters. However, pharmaceutically unacceptable salts are also considered to be within the scope of the present invention, as these compounds may be used to prepare pharmaceutically acceptable salts. For example, pharmaceutically acceptable salts of bendamustine are synthesized from the corresponding compounds containing acid or base groups by conventional chemical methods. These salts are typically prepared, for example, by reacting the free acid or free base forms of these compounds with the corresponding base or acid in stoichiometric amounts in water or in an organic solvent, or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, isopropanol or acetonitrile are generally preferred. Examples of acids useful in forming pharmaceutically acceptable salts of bendamustine include: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, lactic acid, methanesulfonic acid, and p-toluenesulfonic acid. Pharmaceutically acceptable salts of bendamustine may be derived from inorganic or organic bases to yield ammonium salts, alkali metal salts (lithium, sodium, potassium, etc.), alkaline earth metal salts such as calcium or magnesium, aluminum salts, lower alkyl amine salts such as methylamine salts or ethylamine salts, lower alkyl diamine salts such as ethylenediamine salts, ethanolamine salts, N-dialkylene ethanolamine salts, triethanolamine salts, and glucamine salts, and basic salts of amino acids. Especially preferred are the acid salts prepared from hydrochloric, hydrobromic and hydroiodic acid, with the hydrochloride salt being the most preferred pharmaceutically acceptable salt of bendamustine. The pharmaceutically acceptable salts are prepared by conventional techniques well known in the art.

The expression "pharmaceutically acceptable solvate thereof" refers to any pharmaceutically acceptable solvate that is administered to a patient (directly or indirectly) to provide bendamustine. The term also includes pharmaceutically acceptable solvates of bendamustine esters. The solvate is preferably a hydrate, a solvate with an alcohol such as methanol, ethanol, propanol or isopropanol, a solvate with an ester such as ethyl acetate, a solvate with an ether such as methyl ether, ethyl ether or THF (tetrahydrofuran), or a solvate with DMF (dimethylformamide), and among them, a hydrate or a solvate with an alcohol such as ethanol is more preferable. The solvent constituting the solvate is preferably a pharmaceutically acceptable solvent.

It is especially preferred that the active ingredient in the composition of the present invention is bendamustine or a pharmaceutically acceptable salt thereof. Most preferably, the active ingredient is bendamustine hydrochloride.

The dose of the active ingredient in the pharmaceutical composition can be easily determined by the skilled person according to the condition, sex, body weight, body surface area or age of the patient, particularly according to the body weight and body surface area of the patient, and is in the range of 10mg to 1000 mg. Preferably, the daily dose of the active ingredient is from about 50mg to about 1000mg, preferably from about 100mg to about 500 mg. The daily dose may be administered in a single dose or in multiple doses, for example twice or three times daily, most preferably in a single daily dose. The daily dose may be administered once a week or several times a week. The dosage form may comprise a single daily dose amount or a partial amount thereof. Preferably, the dosage form of the present invention comprises from about 10mg to about 1000mg, preferably from about 25mg to about 600mg, more preferably from about 50mg to about 200mg, and most preferably about 100mg of the active ingredient.

The sugar is present in the composition according to the invention in a large amount, preferably in an amount of 2 to 5 times the weight of the active substance. When incorporated into the compositions of the invention, sugars have been shown to have a positive effect on the stability of the active compounds. In addition, it was unexpectedly found that these excipients lead to an increased bioavailability of the active compound, in particular bendamustine hydrochloride, compared to the reference capsules.

Preferred examples of the sugar include mannitol, maltitol, erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose, trehalose, lactitol and dextrose (anhydrous or monohydrate).

In addition to these sugar excipients, the pharmaceutical compositions of the present invention may comprise other excipients, such as lubricants, glidants, fillers (or diluents), binders, and disintegrants, as described in more detail below.

Lubricants are substances that have one or more of the following functions during the preparation of pharmaceutical compositions, especially tablets: preventing the tablet material from adhering to the surfaces of the tablet press parts (hopper, die and punch), reducing inter-particle friction, facilitating tablet ejection from the die and improving the flow rate of the mixture (to be tabletted). The lubricant is typically selected from the group consisting of stearic acid, stearates or stearates, hydrogenated vegetable oils, magnesium oxide, polyethylene glycol, sodium lauryl sulfate and talc, and mixtures thereof. The lubricant is preferably selected from magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, and sodium stearyl fumarate, and mixtures thereof. Stearic acid is the most preferred choice.

In the present application, the term glidant is understood to mean a substance which improves the flow properties of the mixture to be tabletted. For glidants, any suitable glidant may be used, such as talc, silicon dioxide and silica gel (Cab-O-Sil)SyloidAerosil) Starch and calcium silicate. Silicon dioxide is generally used.

In general, the term filler (or diluent) represents those excipients which are used to increase the volume of the sheet to be compressed. This increase in size improves the handling of the solid composition. If the dosage of drug per solid composition is low, or the solid composition is too small, then a filler is generally necessary. Examples of suitable fillers are lactose, sucrose, mannitol, sorbitol, cane sugar (saccharose), starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, calcium carbonate, and any combination thereof. In a preferred embodiment, the filler is selected from the group consisting of lactose, starch, microcrystalline cellulose, microfine cellulose and any combination thereof, most preferably anhydrous lactose and microcrystalline cellulose.

Generally, the term binder is used to impart cohesiveness to the pharmaceutical formulation which ensures that the composition remains intact (especially tablets after compression molding). Different binders are used depending on the compaction technique used (direct compression, dry granulation or wet granulation). For dry compaction techniques (direct compression and dry granulation), suitable binders are lactose, sucrose, mannitol, sorbitol, cane sugar, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, calcium carbonate and any combination thereof. In a preferred embodiment, the binder is selected from the group consisting of lactose, starch, microcrystalline cellulose, microfine cellulose and any combination thereof, most preferably anhydrous lactose and microcrystalline cellulose. In the wet granulation process, the binder may be used either as a solution or in a dry form. As suitable binders there may be mentioned, for example, polyvinylpyrrolidone, dispersible cellulose, hydroxypropyl methylcellulose, starch, pregelatinized starch, partially pregelatinized starch, gum arabic, dextrin, amylopectin and the like. Among these binders, dispersible cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are more preferable.

Disintegrants may be included in pharmaceutical compositions, particularly tablet compositions, to facilitate disintegration or disintegration of the tablet upon contact with aqueous physiological fluids. When a tablet is swallowed, a disintegrant is generally responsible for the rapid disintegration of the tablet upon contact with body fluids (e.g., saliva, gastric fluid, and intestinal fluids). Substances used as disintegrants have been classified by chemical properties into starches, celluloses, crosslinked polymers, and the like. As a result of examining the kind and the amount of the disintegrant used in the practice of the present invention, starch and modified starch (for example, sodium starch glycolate (Primojel)) were found) Sodium carboxymethylcellulose, croscarmellose sodium (Ac-Di-Sol)) Crosslinked polyvinylpyrrolidone, polacrilin potassium salt (Amberlite)IRP88) and low-substituted hydroxypropylcellulose can produce a very good disintegrating effect.

The stability of aqueous bendamustine solutions is strongly affected by the pH value. Substantial hydrolysis of the compound is observed at pH values greater than about 5. When the pH value is > 5, the decomposition proceeds rapidly and, in this pH value range, the content of the obtained by-products is high. The major hydrolysis products are 4- [5- [ (2-chloroethyl) - (2-hydroxyethyl) amino ] -1-methyl-benzimidazol-2-yl ] -butyric acid (HP1), 4- [5- [ bis (2-hydroxyethyl) amino ] -1-methyl-benzimidazol-2-yl ] -butyric acid (HP2) and 4- (5-morpholinyl-1-methylbenzimidazol-2-yl) -butyric acid (HP 3):

orally administered drugs are typically absorbed in the stomach, small intestine and/or large intestine. The pH in the stomach is about 1 to 3.5, in the small intestine about 6.5 to 7.6 and in the large intestine about 7.5 to 8.0. Therefore, for compounds such as bendamustine which tend to degrade in aqueous environments at pH values above 5, it is highly preferred to have them absorbed in the stomach and not excreted to the small intestine, or even the large intestine, to avoid decomposition. There is therefore a need for pharmaceutical compositions wherein bendamustine is completely or at least to a large extent absorbed in the stomach, thereby avoiding or reducing degradation of bendamustine in the small intestine or in the large intestine.

The applicant has unexpectedly found that the problem can be solved by employing the pharmaceutical composition of the present invention, in particular a pharmaceutical composition having the above preferred saccharides. These bendamustine-containing compositions exhibit rapid dissolution behavior, especially such dissolution behavior of bendamustine: bendamustine is dissolved out within 20 minutes, preferably within 10 minutes, preferably within 40 minutes, preferably within 20 minutes, at least 70%, and within 60 minutes, preferably within 30 minutes, at least 80%, and most preferably within 10 minutes, at least 75%, within 20 minutes, at least 85%, and within 30 minutes, at least 90%, as measured in artificial gastric fluid using a paddle apparatus rotating at 50rpm according to the european pharmacopoeia. The artificial gastric juice used herein means a solution prepared by dissolving 2g of sodium chloride in 1000ml of water and then adjusting the pH to 1.5. + -. 0.05 with 5N hydrochloric acid.

The total time for the drug to drain from the stomach to the small intestine is between about 20 minutes and 5 hours, usually between about 30 minutes and 3 hours. Thus, the pharmaceutical compositions of the present invention advantageously reduce the degradation of bendamustine in patients because the bendamustine therein is released and dissolved to a large extent in the stomach, thus allowing for improved bioavailability of the bendamustine-containing compositions of the present invention.

In another aspect of the invention, the solid dosage form pharmaceutical composition may be used for the treatment, induction, rescue treatment, pre-transplant conditioning of stem cells, maintenance treatment, treatment of the residual disease of a human or animal, preferably a human, medical condition selected from Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), hodgkin's disease, non-hodgkin's lymphoma (NHL), multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, and autoimmune diseases.

The invention also includes a method of treating a medical condition in a human or animal body selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelocytic leukemia, acute myelocytic leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer and autoimmune disease comprising administering an effective amount of a pharmaceutical formulation of the invention to a human or animal body in need of treatment. A preferred medical condition is non-hodgkin's lymphoma.

In another aspect of the invention, the pharmaceutical composition may be administered in combination with at least one additional active agent, wherein the additional active agent is administered prior to, simultaneously with, or after administration of the pharmaceutical composition. The at least one further active agent is preferably a CD 20-specific antibody (e.g. rituximab or ofatumumab), an anthracycline derivative (e.g. doxorubicin or daunorubicin), a vinca alkaloid (e.g. vincristine), a platinum derivative (e.g. cisplatin or carboplatin), daphnolide (FK866), YM155, thalidomide and its analogues (e.g. thalidomide or lenalidomide), or a proteasome inhibitor (e.g. bortezomib).

The pharmaceutical compositions of the present invention may also be administered in combination with at least one corticosteroid, wherein the corticosteroid is administered prior to, concurrently with, or subsequent to the administration of the pharmaceutical composition. Examples of such corticosteroids are prednisone, prednisolone and dexamethasone.

The invention is further illustrated by the following examples. It will be apparent to those skilled in the art that these examples are for illustrative purposes only and should not be construed as limiting the invention.

Examples of the present invention

1. Compatibility test

Example 1a

A compatibility test mixture was prepared containing 1: 1 (mass/mass) bendamustine hydrochloride and excipients. The excipient is selected from mannitol and lactose. After preparation, the mixture was charged into Agilent (Agilent) HPLC vials (6ml) made of clear glass and stored under different storage conditions as shown in table 1 below. At defined time points, samples were taken from the storage conditions and checked for purity (HPLC, column: Zorbax bones-RP, 5 μm; column oven temperature: 30 ℃; autosampler temperature: 5 ℃; detector: 254nm) and appearance.

Table 1: storage conditions

^*Storing at 50 deg.C for one month before storing at 70 deg.C

^**Storage at 25 ℃/60% r.h. for one month before storage at 40 ℃/75%

In all these mixtures, the bendamustine hydrochloride content (measured by HPLC) remained almost unchanged and always above 99% for all three storage conditions. For all three storage conditions, almost no hydrolysate HP1 (area% < 0.2) was detected.

Visually inspecting the bendamustine hydrochloride mixture. All tested mixtures were in specification and appeared as white to off-white powders when tested immediately after preparation and after one month storage under all three storage conditions.

Example 1b

To further perform the compatibility test according to the method of example 1a, a mixture was prepared containing 1: 1 (mass/mass) bendamustine hydrochloride and excipients. Said excipient is selected from OpadryEudragitE PO, sodium carboxymethylcellulose (Avicel)RC 591) and Crospovidone (Crospovidone).

In using EudragitIn the case of E PO, the initial amounts of the impurities HP1 (hydrolysate) and BM1DIMER were greatly increased (HP 1: 1.5%, BM1 DIMER: 1%), but under all storage conditions excluding the effect of humidity, a reduction in these impurities during storage could be detected. In the case of crosslinked polyvinylpyrrolidoneA significant increase from 0.1% to 0.4% HP1 could be detected under 40 ℃/75% r.h./vial open storage conditions. Under all other storage conditions (vial closure), no increase in HP1 was detected.

Comprises Eudragit under 70 deg.C/vial closed storage conditionsThe appearance of the mixture of E PO and the mixture containing cross-linked polyvinylpyrrolidone changed. Both mixtures became slightly viscous. Furthermore, the color of the mixture comprising crosslinked polyvinylpyrrolidone changed from white to cream.

Comprises Opadry under 70 deg.C/vial closed storage conditionsAnd a mixture comprising AvicelThe color of the mixture of RC591 also changes to cream.

2. Tablet formulation

Example 2

253g of a mixture containing mannitol (as main excipient) and microcrystalline cellulose, Ac-Di-Sol in the relative amounts indicated in Table 2a below, were prepared by mixing for 15 minutes in a1 liter cube stirrer (Erweka)Colloidal silica, talc and stearic acid. 10.612g of the mixture and 3.0g of bendamustine hydrochloride were then sieved through a 0.425mm sieve, then transferred to a Turbula mixer T2A equipped with a 50ml glass vial, and then mixed at 60rpm for 10 minutes.

The resulting mixture was compression molded into round tablets having the following characteristics:

average diameter: 9.1 mm; average mass: 247.7 mg; average hardness: and 81N.

The tablets were stored at 40 ℃/75% RH (glass vial open) or at 50 ℃ (glass vial closed). The amounts of bendamustine hydrochloride and related substances such as degradation products, by-products of synthesis were measured using HPLC (column: Zorbax Box-RP, 5 μm; column oven temperature: 30 ℃; autosampler temperature: 5 ℃; detector: 254 nm). The results are shown in table 2 b.

^*1: NP 1: 4- [6- (2-chloroethyl) -3, 6, 7, 8-tetrahydro-3-methyl-imidazo [4, 5-h]-[1，4]Benzothiazin-2-yl radical]Butyric acid

BM1 dimer: 4- {5- [ N- (2-chloroethyl) -N- (2- {4- [ 5-bis (2-chloroethyl) amino-1-methylbenzimidazol-2-yl ] butanoyloxy } ethyl) amino ] -1-methylbenzimidazol-2-yl } butanoic acid

BM1 EE: 4- [5- [ bis (2-chloroethyl) amino ] -1-methyl-benzimidazol-2-yl ] butanoic acid ethyl ester

^*2: n.d.: non-detectable, i.e. exceeding the detection limit (area percentage less than 0.05%)

Example 3

Mixtures and tablets were prepared in the same manner as described in example 2, using the compounds and relative amounts described in table 3a below.

The tablet has the following characteristics:

average diameter: 9.1 mm; average mass: 248.9 mg.

The tablets were stored at 40 ℃/75% RH (glass vial open) or at 50 ℃ (glass vial closed). The content of bendamustine hydrochloride and related substances was measured by HPLC as described above. The results are shown in table 3 b:

example 4

Tablets were prepared in the same manner as described in example 2, using the compounds and relative amounts described in table 4a below.

The tablet has the following characteristics:

average diameter: 9.1 mm; average mass: 247.8 mg.

The tablets were stored at 40 ℃/75% RH (glass vial open) or at 50 ℃ (glass vial closed). The amount of bendamustine hydrochloride and related substances was measured by HPLC as described above. The results are shown in table 4 b:

reference example of the prior art

20.0. + -. 1mg of bendamustine hydrochloride was weighed into the capsule body of an empty gelatin hard capsule, and then placed into an Agilent HPLC vial (6ml) made of transparent glass. The capsule is closed by placing the capsule cap over the capsule body and gently pressing. The capsules were stored at 40 ℃/75% RH (glass vial open) or 50 ℃ (glass vial closed). The amount of bendamustine hydrochloride and related substances was measured by HPLC as described above. The results are shown in table 5:

it is evident that, although the capsule formulation was prepared from pure bendamustine hydrochloride without any further processing steps, the stability of the capsule formulation was much poorer compared to the tablet formulation of the present invention. More degradation products were formed both at 40 ℃/75% RH (glass vial open) and within one month of storage at 50 ℃ (glass vial closed). After one month of storage at 40 ℃, 75% RH (relative humidity) with the vial open, the amount of hydrolysate HP1 increased 4-fold. For the closed vials, the HP1 content was even higher, perhaps due to reaction with the capsules. In summary, tablets provide a much more stable solid dosage form compared to capsules.

Example 5

8.0g of hydroxypropylmethylcellulose and 1.5g of PEG 6000 were dissolved in 88.5g of purified water. Thereafter, 2.0g of yellow iron sesquioxide and 0.5g of titanium oxide were dispersed therein to produce a coating liquid. The tablets obtained in example 2 were coated using a film coater in an amount of 3% of the solution per mass of the tablet.

Example 6

Preparation method of 1000 tablets

All core ingredients except colloidal silica and stearic acid were loaded into a Somakon vessel (5L). Bendamustine was added and mixing was performed at 1000rpm for 4 minutes (wiper 10 rpm). The resulting mixture was sieved through a 0.5mm screen. The mixture was refilled into the container and colloidal silica was added. Mixing was carried out under the above conditions for 2 minutes. Thereafter stearic acid was added and mixing was continued for 1 minute. The mixture was then sieved through a 0.5mm screen, reloaded into the container and mixed for an additional 30 seconds, all under the same conditions as described above.

Compression molding the mixture into round tablets having the following characteristics:

average diameter: 9.5 mm; average mass: 254.6mg (starting) to 257.2mg (final); friability 0.1%; average hardness: 122N (start) to 128N (final).

Then Opadry is adoptedDispersion the tablets were film coated until the mass increased by 5%.

The average mass of the film-coated tablets was 268.4 mg.

The core and film coated tablets were stored in closed amber glass vials at 40 ℃/75% RH. As described above, the amount of bendamustine hydrochloride and related substances such as degradation products, by-products of synthesis, and the like were measured by HPLC. The results are shown in table 6b.1 and table 6 b.2.

^*3: unidentified compound peak at relative retention time of 0.69 relative to the main peak

Example 7

Preparation method of 1000 tablets

All core ingredients except colloidal silica and stearic acid were loaded into a Somakon vessel (5L). Bendamustine was added and mixing was performed at 1000rpm for 4 minutes (wiper 10 rpm). The resulting mixture was sieved through a 0.5mm screen. The mixture was refilled into the container and colloidal silica was added. Mix for 2 minutes under the above conditions. Thereafter stearic acid was added and mixing was continued for 1 minute. The mixture was then sieved through a 0.5mm screen, reloaded into the container and mixed for an additional 30 seconds, all under the same conditions as described above.

Compression molding the mixture into round tablets having the following characteristics:

average diameter: 9.5 mm; average mass: 262.4mg (initial) to 254.4mg (final); friability: 0.1% (initial) to 0.2% (final); average hardness: 98N (initial) to 91N (final).

Followed by EudragitDispersion the tablets were film coated until the mass increased by 3%.

The average mass of the film-coated tablets was 273.5 mg.

The core and film coated tablets were stored in closed amber glass vials at 40 ℃/75% RH. The content of bendamustine hydrochloride and related substances was measured by HPLC as described above. The results are shown in tables 7b.1 and 7 b.2:

example 8

Preparation method of 1000 tablets

All core ingredients except colloidal silica and stearic acid were loaded into a Somakon vessel (2.5L). Bendamustine was added and mixing was performed at 1000rpm for 4 minutes (wiper 10 rpm). The resulting mixture was sieved through a 0.5mm screen. The mixture was refilled into the container and colloidal silica was added. Mixing was carried out under the above conditions for 2 minutes. Thereafter stearic acid was added and mixing was continued for 1 minute. The mixture was then sieved through a 0.5mm screen, reloaded into the container and mixed for an additional 30 seconds, all under the same conditions as described above.

Compression molding the mixture into round tablets having the following characteristics:

average diameter: 9.5 mm; average mass: 252.2mg (start) to 250.7mg (end); friability: 0.1% (initial) to 0.2% (final); average hardness: 65N (initial) to 73N (final).

Followed by EudragitDispersion the tablets were film coated until the mass increased by 3%.

The average mass of the film-coated tablets was 253.6 mg.

The core and film coated tablets were stored in closed amber glass vials at 40 ℃/75% RH. The amount of bendamustine hydrochloride and related substances was measured by HPLC as described above. The results are shown in tables 8b.1 and 8 b.2:

example 9

The preparation method of the 600 tablet preparation PF1 comprises the following steps:

33.06g bendamustine, 111.60g dextrose, 40.92g lactose, 11.22g microcrystalline cellulose, and 1.20g magnesium stearate were weighed and transferred to a double-layer polyethylene bag and mixed for 5 minutes. The powder mixture was then transferred to the hopper of an eccentric tablet press (Korsch EK0) and compression molded into round tablets with the following characteristics: average diameter: 10.0 mm; average mass: 336.9mg (initial) to 335.98 (final); friability: 0.15 percent; average hardness value: 69.25N (initial) to 68.60N (final).

Then in a coating pan (4M8Formate Pancoat) with 9% white Opadry (Opadry)TM White) aqueous suspension the cores were coated and dried. The average mass of the tablets was 342.42 mg. The tablets were then filled into amber glass vials closed with screw stoppers and stored at 40 ℃/75% RH.

The preparation method of the 600 tablet preparation PF2 comprises the following steps:

33.06g bendamustine, 111.42g lactose, 39.60g trehalose, 12.60g crospovidone, and 1.32g magnesium stearate were weighed and transferred to a double-layer polyethylene bag and mixed for 5 minutes. The powder mixture was then transferred to the hopper of an eccentric tablet press (Korsch EK0) and compression molded into round tablets with the following characteristics: average diameter: 10.0 mm; average mass: 332.95mg (starting) to 332.12 (final); friability: 0.3 percent; average hardness value: 65.9N (initial) to 59.0N (final).

Then in a coating pan (4M8Formate Pancoat) with 9% OpadryThe cores were coated with an aqueous suspension of TM White and dried. The average mass of the tablets was 340.1 mg. The tablets were then filled into amber glass vials closed with screw stoppers and stored at 40 ℃/75% RH.

Preparation method of the preparation PF 3:

sorbitol and anhydrous dextrose were weighed. 140.64g of sorbitol were dissolved in 105.48g of purified water, and 659.36g of dextrose were subsequently granulated in a fluid bed granulator (4M8ForMate fluid bed) using the resulting solution. Thereafter, the granules were dried at 60 ℃ and sieved through a 850 μm sieve.

33.06g of bendamustine hydrochloride, 149.82g of sorbitol/dextrose granules, 13.8g of microcrystalline cellulose and 1.32g of magnesium stearate were weighed out and transferred to a double-layer polyethylene bag to be mixed for 5 minutes. The powder mixture was then transferred to the hopper of an eccentric tabletting machine (Korsch EK0) and compression molded into round tablets having an average diameter of 10.0 mm. The average mass of the tablets was 335.99mg (starting) to 339.50 (final); the friability is 0%; the average hardness values ranged from 125.60N (initial) to 129.7N (final). The tablets were then subjected to a two step pre-treatment process (only on selected batches): the tablets were placed at 25 ℃/60% r.h. for two hours, followed by two hours at 40 ℃.

Then in a coating pan (4M8Formate Pancoat) with 9% OpadryThe tablets were coated with an aqueous suspension of TM White. The average mass of the tablets was 341.43 mg. The tablets were then filled into amber glass vials closed with screw stoppers and stored at 40 ℃/75% RH.

The amount of bendamustine hydrochloride and related substances in the preserved film-coated tablets was measured by HPLC as described above. The results are shown in tables 9b.1 to 9 b.3:

3. dissolution test

Example 10

The tablet formulations of examples 2 and 3 were subjected to dissolution test in artificial gastric fluid when T ═ 0. The dissolution samples were tested for analysis by HPLC (column: Zorbax bones-RP, 5 μm; column oven temperature: 30 ℃; autosampler temperature: 5 ℃; detector: 254 nm). Artificial gastric juice (pH 1.5) was prepared by the following steps: 2g of sodium chloride p.A. are dissolved in 1000ml of water and the pH is adjusted to 1.5. + -. 0.05 with 5N hydrochloric acid. Dissolution tests were carried out according to the european pharmacopoeia 6.0, chapter 2.9.3, using apparatus 2 (paddle apparatus). The paddle speed was 50rpm, the temperature was 37 ℃. + -. 0.5 ℃ and the amount of dissolution medium was 500 ml.

The tablet formulation results for example 2 (tablet formulation 1) and example 3 (tablet formulation 2) are shown in table 10a below:

table 10 a:

the results of the same dissolution test performed on the coated tablet formulations of example 6, example 7 and example 8 when T ═ 0 are shown in table 10b below:

TABLE 10b

The corresponding dissolution data for the tablets of example 9 are:

as can be seen from the above, all tablet formulations of the present invention show rapid dissolution behavior of bendamustine. In particular, the formulations of the present invention exhibit bendamustine dissolution behavior as defined herein before.

4. In vivo assay

Animal bioavailability studies of bendamustine in beagle dogs: outline of PK study

Study experiment 1

The study objective was to determine the bioavailability of bendamustine at 1 dose (i.e., 50mg) in 3 tablet formulations (T1-3) and 1 capsule formulation (C) (4 total oral formulations): AUC and Cmax

Total number of animals required: 16 pieces of

Basic design:

cross-over design, 8 animals per branch (arm):

table 11 a: phase 1 (single dose tablet, or capsule, day 1):

elute one week (wash-out)

Table 11 b: phase 2 (one week after phase 1, single dose of each of the following formulations, day 8):

elute in one week

Table 11 c: phase 3 (one week after phase 2, single dose of each of the following formulations, day 15):

study experiment 2

The objective of the study was to determine the bioavailability of bendamustine at 1 dose (i.e., 50mg) in 1 tablet formulation T4 and 1 capsule formulation (C) (3 total oral formulations): AUC and Cmax

Total number of animals required: 16 pieces of

Basic design:

crossover design, 8 animals per branch:

table 12 a: stage 1 (Single dose capsule, day 1)

Elute in one week

Table 12 b: phase 2 (one week after phase 1, single dose of each of the following formulations, day 8):

example 11

The coated tablet of example 9 (formulation 3, with Opadry) containing 50mg bendamustine was orally administered to male and female dogsCoating, tablet T4) and compared to the capsules of the reference example.

The mean plasma concentrations of the capsule formulation and the coated tablet of example 9 are shown over time in figure 1.

Example 12

The coated tablets of examples 6, 7 or 8 (tablets T1 to T3) containing 50mg bendamustine were orally administered to male and female dogs, and compared to the capsules of the reference example.

The mean plasma-time relationship of the capsule formulations and the coated tablets of examples 6-8 is shown in figure 1.

The experiments were performed for the following:

-assessing which sugar or sugar mixture is suitable for obtaining a chemically stable tablet with fast dissolution behaviour and a hardness value suitable for coating;

-evaluating the compatibility between API and excipient;

-developing placebo and API containing batches by studying the following different preparation processes: dry granulation, direct pressing and wet granulation;

-evaluating different bendamustine hydrochloride/sugar weight ratios;

-assessing the effect of sugar purity on bendamustine hydrochloride impurity formation;

study of the effect of moisture content on the technical performance and stability of the tablets prepared;

use of the commercially available lyophilized bendamustine hydrochloride product (Ribomustin)) Tablets were prepared and the properties of these tablets were compared to those of tablets prepared using a comparable amount of mannitol and bendamustine hydrochloride.

Tablets of the invention containing 50mg bendamustine (55 mg for bendamustine hydrochloride) were prepared using the following sugars.

Watch 13

The quality of the prepared batches was assessed by observing physical appearance, identification tests (HPLC), dissolution tests, content and related substance analysis (HPLC), content uniformity tests (HPLC), hardness tests and water content (Karl Fischer method). The batches were filled into amber glass bottles and accelerated stability studies were performed under storage conditions as detailed in the table below. For each batch prepared containing API, some tablets were stored at 5 ℃ as backup samples.

Next, various excipients associated with the tablet manufacturing process were investigated. By using these excipients, several placebo preparation trials were carried out using dry granulation, thus obtaining preliminary information about the preparation methods suitable for obtaining tablets with good quality.

Two types of disintegrants are used: microcrystalline cellulose (Avicel) as a standard disintegrantPH 112), and Crospovidone (Crospovidone) used only for lot D001T/002). Croospovidone was chosen for batch D001T/002 (filler: lactose anhydrous)Based on the similarity between this formulation and the prototype formulation of example 9. For all batches prepared, magnesium stearate was used as a lubricant. The dry granulation preparation process for placebo testing included the following steps:

1. sugar and a partial amount of lubricant (83.3% w/w of the total) were accurately weighed and then mixed in a polyethylene bag for 2 minutes.

2. The resulting mixture was compacted using a tablet press equipped with 18mm diameter punches.

3. The resulting billet (slug) was sieved using a 850 micron screen.

4. The granules were weighed and mixed with disintegrant and remaining amount of lubricant (16.7% w/w) in a polyethylene bag for 2 minutes before tabletting with a 10mm diameter punch.

Tables 14 and 15 summarize the composition of each placebo formulation and the results of the analytical tests performed on the final mixture and tablets. The results observed during the preparation of the placebo batches and/or during their analytical characterisation are shown in table 16.

The results of the analyses and physical tests carried out on placebo batches D001T/001, D001T/002, D001T/004, D001T/013, D001T/015 show that these formulations are suitable for preparation by dry granulation and for further studies by addition of API. All other formulations are characterized by a difficulty in compacting the powder and by a high friability of the tablets in the case of tablets obtained.

Lot D001T/005 (Filler: β -Cyclodextrin) showed good behaviour during dry preparation, high hardness, low friability, but long disintegration times by using superdisintegrants (Croppovidone)) And an API was added to further study this formulation (see below).

The prepared batches are granulated by a dry method according to the weight ratio of the bendamustine hydrochloride to the sugar of 1: 5

A placebo formulation rated more suitable for preparing tablets containing an Active Pharmaceutical Ingredient (API) by dry granulation was modified to contain an API, and two API/sugar weight ratios were explored: 1: 5 and 1: 2.

In this paragraph, a formulation containing API/sugar in a weight ratio of 1: 5 is described.

Two types of disintegrants are used: microcrystalline cellulose (Avicel) as a standard disintegrantPH 112), and Crospovidone (Crospovidone) used only for lot D001T/022). For all batches prepared, magnesium stearate was used as a lubricant.

The process for preparing the API-containing batch by dry granulation comprises the following steps:

1. sugar, a partial amount of lubricant (83.3% w/w of the total amount) and bendamustine hydrochloride were accurately weighed and then mixed in a double-layer polyethylene bag for 5 minutes.

2. The powder mixture was compressed using a tablet press equipped with 18mm diameter punches.

3. The resulting billet was sieved using a 850 micron sieve to obtain granules.

4. The granules were weighed and mixed with disintegrant and remaining amount of lubricant (16.7% w/w) in a double layer polyethylene bag for 5 minutes.

5. The resulting mixture was tableted using a 10mm diameter punch.

Table 17 summarizes the composition of each API-containing formulation prepared, and the results of analytical tests performed on the final mixtures containing the API; table 18 summarizes the results of the analytical tests performed on the obtained articles.

TABLE 17 Dry granulation-API/sugar weight ratio 1: 5. Composition and analytical results of the final mixture of API-containing batches.

TABLE 18 Dry granulation-API/sugar weight ratio 1: 5. Analysis results of the tablets of the API-containing batches.

The results of analytical tests carried out on the final mixture and on the resulting preparation (mainly content uniformity and purity) are in most cases good. All API-containing batches showed satisfactory quality uniformity, API content uniformity and low impurity content. The impurity profile of all formulations met the API specification (see specification limits in the table) and therefore no degradation occurred during the preparation process.

Both API-containing batches showed low values in the API analysis, which results can be attributed to the small batch size as well as losses during preparation and samples used for IPC of the final mixture.

API-containing batches prepared by dry granulation with a weight ratio API/sugar of 1: 2

All sugars previously investigated for the preparation of 1: 5 weight ratio API/sugar tablets using dry granulation were again rated at a 1: 2 ratio.

The preparation process is as described above. In this case, the resulting mixture was tabletted using an 8mm diameter punch.

Two types of disintegrants are used: microcrystalline cellulose (Avicel) as a standard disintegrantPH 112), and Crospovidone (Crospovidone) used only for lot D001T/105). For this batch, we looked at AvicelPH 112 and CroospovidoneThe use of (2) was investigated. Croospovidone was selected based on the cyclodextrin-based formulation previously prepared by dry granulation at a 1: 5 API/sugar ratio (see previous results)

Tables 19 and 20 summarize the composition of each API-containing formulation prepared by dry granulation at a weight ratio of API/sugar of 1: 2, and the results of the analytical tests performed on the final mixture and tablets. All API-containing batches showed suitable quality uniformity, API content uniformity and low impurity content. In most cases, the friability and hardness values meet specifications. In the case of batches D001T/093, D001T/095 and D001T/096, the results of the dissolution test on 6 tablets showed high RSD outside the specification values, the test extending to a sample of 12 tablets.

In two disintegrating agents (Avicel)PH 112 and Crospovidone) The lower cyclodextrin-based tablets all showed good properties.

TABLE 19 Dry granulation-API/sugar weight ratio 1: 2. Composition and analytical results of the final mixture of API-containing batches.

API-containing batches prepared by direct compression were used at a weight ratio of API/sugar of 1: 5.

Studies on saccharides having characteristics suitable for preparation by dry granulation using direct compression have led to the development of tablets having an API/sugar ratio of 1: 5.

Two types of disintegrants are used: microcrystalline cellulose (Avicel) as a standard disintegrantPH 112), and Crospovidone (Crospovidone) used only for lot D001T/029)。

The preparation process comprises the following steps:

1. the API and excipients were weighed.

2. The stock was transferred to a double-layer polyethylene bag and mixed for about 5 minutes until a homogeneous powdered mixture was obtained.

3. The powdered mixture is transferred to the tablet press hopper.

4. The powdered mixture was compression molded using an eccentric tablet press equipped with a 10mm diameter punch.

The characteristics of the API-containing batches prepared using direct compression are shown in the table below.

TABLE 21 direct compression API/sugar weight ratio 1: 5. Composition and analytical results of the final mixture of API-containing batches.

The results of the analytical tests are shown in Table 22.

TABLE 22 direct compression API/sugar weight ratio 1: 5. Analysis results of the tablets of the API-containing batches.

As shown in the above table, none of the tablets comprising API prepared by direct compression showed any critical difference from the tablets prepared by dry granulation, except that batch D001T/030 (filler: sucrose 97% + maltodextrin 3%) showed a non-uniform API content and a slightly increased friability value.

And (3) wet granulation:

placebo exploratory test

According to the results obtained in the first and second parts of the protocol, a wet granulation study was carried out on those sugars which were not suitable for dry granulation or direct compression.

The protocol for studying the wet granulation technique is shown below.

Each sugar was granulated according to the procedure described in the flow chart of figure 2. At the end of each step, the wet granulated sugar was dried and subjected to a compression moulding test to assess whether the granules were suitable for tabletting. Placebo batches were prepared only for granulated sugar for which compression molding trial results were suspect. The composition of the placebo trial and the associated analysis results are shown in table 23.

Placebo batches were prepared according to the following steps:

1. the sugars were wet granulated with water or sorbitol solution using a fluid bed or high shear granulator (see flow sheet and table 23 for the wet granulation preparation test above).

2. The wet granulated sugar is dried in a fluid bed granulator or in an oven.

3. The granulated sugar was sieved by using 850 micron and 710 micron sieves.

4. All ingredients of the respective formulations were weighed and mixed in a polyethylene bag for 2 minutes.

5. The powdered mixture was compression molded using an eccentric tablet press equipped with a 10mm diameter punch.

For all batches prepared, Avicel PH 112 and magnesium stearate were used as disintegrant and lubricant, respectively.

At a weight ratio of API to sugar of 1: 5, usingAPI-containing batches prepared by wet granulation

All those saccharides that showed unsuitability for the preparation of tablets by dry granulation or direct compression techniques were subjected to manufacturing trials including the wet granulation process.

The preparation steps for these experiments performed on a laboratory scale are summarized below:

1. the sugars were wet granulated with water or sorbitol solution using a fluid bed or high shear granulator (see flow sheet and table 24 for the wet granulation preparation test above).

2. The wet granulated sugar is dried in a fluid bed granulator or in an oven.

3. Sieving was performed through 850 micron and 710 micron sieves.

4. The API and excipients were weighed and mixed in a double polyethylene bag for 5 minutes.

5. The powdered mixture was compression molded using an eccentric tablet press equipped with a 10mm diameter punch.

For all batches prepared, Avicel PH 112 and magnesium stearate were used as disintegrant and lubricant, respectively.

Tables 24 and 25 set forth the composition of each of the API-containing formulations prepared by wet granulation, and the results of the analytical tests conducted on the final blends and tablets

In most cases, the results of the analytical tests carried out on the final mixture and on the finished product are in compliance with the specifications. No degradation occurred during the preparation process.

Of the sugars studied, only fructose MS (Galam) was not suitable for processing by wet granulation: the friability of API-containing lot D001T/047 was high, while lot D001T/082 showed friability and hardness values outside specification.

Batches D001T/060, D001T/061, D001T/082 and D001T/086 had low values in the API analysis, whereas for batches D001T/082 and D001T/086, despite the use of 850 and 710 micron screens to screen the particles, the content uniformity was not met. This result may be attributed to poor powder mixing.

API-containing batches prepared by wet granulation with a weight ratio API/sugar of 1: 2

All sugars previously investigated to prepare 1: 5 weight ratio API/sugar tablets using wet granulation were again rated at a 1: 2 ratio.

At the 1: 2 ratio, fructose was not rated, as the resulting granules were not suitable for tableting.

For all batches prepared, Avicel PH 112 and magnesium stearate were used as disintegrant and lubricant, respectively.

To improve the uniformity of the API content, the API-containing batches were prepared using the following steps:

1. the sugar was wet granulated using the procedure previously optimized.

2. A mixture containing the API was prepared.

3. The mixture is subjected to dry granulation (billet preparation → billet screening).

4. The resulting mixture was tabletted with an 8mm diameter punch.

Step 3 (dry granulation of the mixture) is as described above.

Tables 26 and 27 show the composition and analytical results of API-containing batches prepared by using wet granulated sugar at an API/sugar weight ratio of 1: 2. In most cases, the friability is out of specification. The weight change of the API/sugar did not jeopardize the technical performance of batch D001T/084 (bulking agent: granulated mannitol).

Effect of API/mannitol weight ratio

Mannitol-based tablets were prepared to study the following API/mannitol ratio: 1: 0.01, 1: 0.1, 1: 0.5, 1: 1.7, 1: 4, 1: 5, 1: 6 and 1: 10. Formulations with a weight ratio API/mannitol of 1: 5 (standard formulations) were reported above.

For the preparation of these batches, Avicel PH 112 and magnesium stearate were used as disintegrant and lubricant, respectively. Regarding the preparation process, the wet granulated mannitol, bendamustine hydrochloride and excipients were precisely weighed for the ratios of 1: 1.7, 1: 4, and 1: 6, and mixed in a double-layer polyethylene bag for 5 minutes. For batch D001T/110 (1: 10 ratio), a premix was performed. In this case, bendamustine hydrochloride was mixed with half the amount of the excipient mixture for 5 minutes. Thereafter, the resulting mixture was added to the remaining amount of excipient and mixed for another 5 minutes. The final mixture was tabletted using a tablet press equipped with suitable punches (8 mm punches for 1: 1, 1: 1.7 and 1: 2 ratios, 10mm punches for 1: 4 and 1: 6 ratios, 12mm punches for 1: 7 ratios and 14mm punches for 1: 10 ratios).

For the ratios of 1: 0.01, 1: 0.1 and 1: 0.5, we used the above reported preparation procedure (wet granulation followed by dry granulation of the sugar) to improve the API content uniformity. The resulting mixture was tableted using a 6mm diameter punch.

The following tables (tables 28 and 29) summarize the compositions and analytical results of API-containing formulations prepared to study the effect of different API/mannitol ratios. Batches D001T/111, D001T/083 and D001T/106 showed high friability, whereas batches D001T/106, D001T/108 and D001T/109 did not meet the content uniformity, deviating from the trend of the data obtained before. This result may be attributed to the fact that these batches were prepared by using many novel bendamustine hydrochloride (cat # F08-05873) which may have different physical properties.

Carbohydrate combination study

Tables 30 and 31 show the results of the study on saccharide combinations.

The following combinations were studied:

1: 1 monosaccharide/disaccharide

(^*) Mannitol (Pearlitol 200 SD)/lactose anhydrous (SuperTab 21AN) sorbitol (Neosorb P60W)/maltose (Sunmalt S)

Oligosaccharide/monosaccharide 1: 1

(^*) D-melezitose monohydrate/(^*) Anhydrous dextrose ST 0.5

(^*) Granulated raffinose pentahydrate/(^*) Granulated mannitol (Pearlitol 200SD)

Oligosaccharide/disaccharide 1: 1

(^*) Granulated raffinose pentahydrate/lactose monohydrate (Supertab 14SD)

beta-cyclodextrin (Klepose DC)/sucrose (EV Saccharomyces)

(^*) These sugars are granulated by wet granulation (see page 32).

The preparation process comprises direct compression of the raw or granulated sugar.

These batches were prepared using Avicel PH 112 and magnesium stearate as disintegrants and lubricants, respectively, by performing the following steps:

1. the sugar (or granulated sugar), bendamustine hydrochloride, and excipients were accurately weighed and mixed in a double-layer polyethylene bag for 5 minutes.

2. The resulting mixture was tableted using a 10mm diameter punch.

TABLE 30 saccharide combination study. Composition and analytical results of the final mixture of API-containing batches.

Tablets prepared for studying the saccharide combination showed good properties overall. However, lot D001T/102 (raffinose pentahydrate/mannitol 200SD) showed high friability, while lots D001T/100 and D001T/049 did not have uniform API content.

Example 14 Freeze-dried bendamustine hydrochloride (Ribomustin) and bendamustine hydrochloride/mannitol tablets (API/sugar weight ratio 1: 1.2)

The commercially available intravenous preparation (Ribomustin) is used) The resulting lyophilizate, or wet granulated mannitol and bendamustine hydrochloride, were used to prepare tablets containing bendamustine hydrochloride/mannitol in a 1: 1.2 weight ratio.

The preparation was carried out according to the following experimental procedure: lyophilizing the powder from RibomustinThe vial was removed and sieved using a 850 micron mesh. The resulting powder and lubricant (magnesium stearate) were accurately weighed and mixed in a polyethylene bag for 5 minutes. The mixture was slowly transferred into the compression chamber of a tablet press and manually compressed using an 8mm diameter punch to obtain a small billet. The billet was sieved using a 850 micron mesh and the resulting granules were hand pressed using an 8mm diameter punch.

Bendamustine hydrochloride/mannitol tablets were prepared using the same procedure as described above in this example.

The composition of the formulation is shown in table 32.

Table 32 Ribomustin and bendamustine/mannitol tablets. Composition of the final mixture of API-containing batches.

(. about.) 45.16% bendamustine hydrochloride and 54.20% mannitol

Table 33 shows data comparing tablets obtained using the lyophilized bendamustine hydrochloride/mannitol mixture to tablets obtained using the non-lyophilized bendamustine hydrochloride/mannitol mixture.

Table 33 Ribomustin and bendamustine/mannitol tablets. Analytical results of tablets containing API batches

With the impurity profile of bendamustine hydrochloride API as a reference indicator (see specification limits in the table), batch D001T/125 showed impurity HP1 to be out of specification. Dissolution test results highlighted that, although the dissolution behavior of the tablets containing the lyophilized bendamustine hydrochloride/mannitol mixture was faster after 10 minutes, the dissolution behavior of both formulations met the current specifications after 30 minutes. Lot D001T/126 was out of specification for friability and Lot D001T/125 was not tested due to the lack of sufficient amount of material.

Industrial applications

The pharmaceutical compositions of the present invention exhibit a number of advantages. The patient can easily use the pharmaceutical composition without the help of supervising medical staff. It may no longer be necessary to go through the time-consuming procedure of hospital visits, thereby improving patient compliance.

Since the dosage form is solid, it can be swallowed, which means that the patient does not need to wait until the active ingredient is dissolved. In addition, since the formulation has good stability, the formulation can be easily stored at room temperature and does not require any special storage conditions.

By using the dosage form of the present invention, the volume of the dosage form can be significantly reduced. The reduction in size is advantageous both from a production and handling perspective and from a patient compliance perspective.

The pharmaceutical compositions exhibit high in vitro dissolution rates which reduce bendamustine degradation in vivo, thereby resulting in improved in vivo bioavailability of bendamustine.

Claims (14)

1. a pharmaceutical composition in solid dosage form for oral administration comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as active ingredient and at least one pharmaceutically acceptable sugar excipient being a pharmaceutically acceptable sugar selected from the group consisting of one or more of mannitol, maltitol, erythritol, xylitol, sorbitol, maltose, trehalose, lactitol, dextrose, β -cyclodextrin, D-raffinose pentahydrate and D-melezitose monohydrate, wherein the weight ratio of said active ingredient to said sugar excipient is in the range of 1: 1 to 1: 5, characterised in that said pharmaceutical composition is in the form of a tablet, granule or pill.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the active ingredient to the sugar excipient is from 1: 2 to 1: 5.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the tablets or tablet pellets, the granules or the pellets have a coating.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the active ingredient is bendamustine hydrochloride.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising 10 to 1000mg of the active ingredient and 30 to 5000mg of the sugar excipient.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the sugar excipient is selected from anhydrous dextrose, dextrose monohydrate, lactitol monohydrate, and maltose monohydrate.

7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable lubricant, filler and/or disintegrant.

8. The pharmaceutical composition of claim 1 which exhibits bendamustine dissolution behavior such that: the bendamustine is at least 60% dissolved in 10 minutes, at least 70% dissolved in 20 minutes and at least 80% dissolved in 30 minutes measured according to the european pharmacopoeia in 500ml of dissolution medium at pH 1.5 using a paddle apparatus rotating at 50 rpm.

9. The pharmaceutical composition according to any one of claims 1 to 8, for use in the treatment of a medical condition selected from: chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelocytic leukemia, acute myelocytic leukemia, hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, and autoimmune disease.

10. The pharmaceutical composition according to any one of claims 1 to 8, or a pharmaceutical composition for use according to claim 9, which composition is administered in combination with at least one further active agent, wherein the further active agent is administered prior to, simultaneously with or subsequent to the administration of the pharmaceutical composition.

11. The pharmaceutical composition of claim 10, wherein the additional active agent is a CD 20-specific antibody, an anthracycline derivative, vinblastine, or a platinum derivative.

12. The pharmaceutical composition of claim 11, wherein the CD 20-specific antibody is rituximab; the anthracycline derivative is adriamycin or daunorubicin; the vinblastine is vincristine; and the platinum derivative is cisplatin or carboplatin.

13. The pharmaceutical composition according to any one of claims 1 to 8, or 10 to 12, or the pharmaceutical composition for use according to claim 9, which composition is administered in combination with at least one corticosteroid, wherein the corticosteroid is administered before, simultaneously with or after administration of the pharmaceutical composition.

14. The pharmaceutical composition of claim 13, wherein the corticosteroid is prednisone or prednisolone.