HK1242993B - A pharmaceutical composition in a solid dosage form suitable for oral administration - Google Patents

Description

Solid dosage pharmaceutical composition for oral administration

Technical Field

The present invention relates to a solid dosage form for oral administration comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof.

Background Art

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

Bendamustine does not appear to confer any cross-resistance to other alkylating agents, which may be an advantage in administering chemotherapy to patients who have already received alkylating agents.

Bendamustine was originally synthesized in the German Democratic Republic (GDR). Bendamustine hydrochloride was the active ingredient in commercial products sold under the trade name Bendamustine from 1971 to 1992. Since then, Bendamustine hydrochloride has been sold in Germany under the trade name Bendamustine and is widely used to treat chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and multiple myeloma.

The commercially available product consists of a lyophilized powder of bendamustine hydrochloride that is reconstituted with water for injection to produce a concentrate. This concentrate is then diluted with a 0.9% aqueous sodium chloride solution to produce a final solution for infusion. The final solution is administered to patients via intravenous infusion over a period of approximately 30 to 60 minutes.

Hydrolysis of the di-2-chloroethylamino group of bendamustine in water can lead to reduced efficacy and the formation of impurities (B. Maas et al. (1994), Pharmazie 49:775-777). Therefore, the lyophilized powder must be administered immediately after reconstitution (usually in a hospital or at least under medical supervision). In addition, it has been reported that the reconstitution process is difficult. The process may take more than 30 minutes. In addition, for the medical professional responsible for reconstitution of the product, reconstitution in a two-step process is tedious and time-consuming.

Preiss et al. (1985) (Pharmazie 40:782-784) compared the pharmacokinetics of bendamustine hydrochloride in the plasma of seven patients after intravenous and oral administration of doses ranging from 4.2 mg/kg to 5.5 mg/kg. An intravenous infusion of a commercially available product was administered over 3 minutes, while an equivalent oral dose was taken in the form of capsules containing 25 mg of bendamustine hydrochloride. The number of capsules taken by the patients ranged from 10 to 14. Following oral administration, maximum plasma levels were detected within 1 hour. The calculated mean oral bioavailability was 57%, ranging from 25% to 94%, indicating significant interindividual variability.

Weber (1991) (Pharmazie 46(8):589-591) studied the bioavailability of bendamustine hydrochloride in B6D2F1- mice and found that the drug was incompletely absorbed from the gastrointestinal tract, resulting in a bioavailability of only about 40%.

Patent document US 2006/0128777 A1 describes methods for treating cancer, generally characterized by anti-death cell effects and compositions containing bendamustine. These compositions include oral solid dosage forms in the form of capsules, tablets, pills, powders, or granules, in which the active compound may be mixed with at least one inert excipient (e.g., sucrose, lactose, or starch). However, specific compositions are not exemplified.

Given the stability issues with commercially available intravenous formulations once reconstituted with water, and to improve patient compliance, there has long been a need for a stable oral dosage form containing bendamustine that is easy to administer to patients and provides enhanced bioavailability with reduced variability compared to known oral dosage forms.

SUMMARY OF THE INVENTION

To address the above-mentioned issues, the present inventors have conducted extensive research and ultimately succeeded in obtaining the stable pharmaceutical compositions of the present invention. These compositions are suitable for oral administration and comprise: bendamustine or a pharmaceutically acceptable ester, salt, or solvate thereof as an active ingredient; and at least one pharmaceutically acceptable excipient. These compositions exhibit improved dissolution behavior.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the mean plasma concentration (tablets versus capsules) versus time curves obtained after administration of bendamustine hydrochloride to puppies in the form of prior art capsules and the 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 bendamustine concentration than the prior art capsules.

FIG2 shows a flow chart of the wet granulation preparation experiment.

Detailed Description of the Invention

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 monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides, and sugar alcohols. Preferably, the weight ratio of the active ingredient to the excipient is in the range of 1:1 to 1:5, preferably in the range of 1:2 to 1:5, and more preferably a ratio selected from 1:5 and 1:2.

In one embodiment, the present invention relates to a solid dosage pharmaceutical composition for oral administration, comprising: bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is a pharmaceutically acceptable sugar selected from the group consisting of one or more monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides and sugar alcohols, wherein the weight ratio of the active ingredient to the excipient is within the range of 1:1.

In a further embodiment, the present invention relates to a solid dosage pharmaceutical composition suitable for oral administration, 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 monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides and sugar alcohols, wherein the weight ratio of the active ingredient to the saccharide excipient is in the range of 1:2 to 1:5, and the composition exhibits the following bendamustine dissolution behavior: at least 60% of the bendamustine is dissolved within 20 minutes, at least 70% is dissolved within 40 minutes, and at least 80% is dissolved within 60 minutes, as measured in 500 ml of dissolution medium at a pH of 1.5 according to the European Pharmacopoeia using a paddle apparatus at a rotation speed of 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 monosaccharides, disaccharides 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 the following bendamustine dissolution behavior: at least 60% of bendamustine is dissolved within 20 minutes, at least 70% is dissolved within 40 minutes, and at least 80% is dissolved within 60 minutes, as measured in 500 ml of dissolution medium at a pH of 1.5 according to the European Pharmacopoeia using a paddle apparatus at a speed of 50 rpm.

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

It has been found that if the following pharmaceutically acceptable sugars are used as excipients in a pharmaceutical composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, the composition achieves particularly good performance in terms of stability, tableting properties, dissolution and impurity formation, wherein the pharmaceutically acceptable sugars are selected from the group consisting of one or more monosaccharides, disaccharides, oligosaccharides, cyclic oligosaccharides, polysaccharides and sugar alcohols, and preferably from the group consisting of one or more monosaccharides, disaccharides and oligosaccharides. The above sugars result in the composition exhibiting the following bendamustine dissolution behavior: at least 60% of the bendamustine is dissolved within 20 minutes, at least 70% within 40 minutes and at least 80% within 60 minutes, as measured in 500 ml of dissolution medium at a pH of 1.5 according to the European Pharmacopoeia using a paddle apparatus at a rotation speed of 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.

In particular, it has been found that specific sugars are associated with particularly favorable stability and dissolution properties of pharmaceutical compositions. Preferred sugars in the compositions of the present invention include anhydrous dextrose, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, anhydrous lactose, lactose monohydrate, maltitol, xylitol, sucrose, 97% sucrose + 3% maltodextrin, β-cyclodextrin, D-raffinose pentahydrate, D-melezitose monohydrate, and microcrystalline cellulose. The pharmaceutical compositions of the present invention exhibit favorable tableting properties, rapid dissolution behavior, and pharmaceutically suitable stability.

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

A further preferred embodiment of the present invention is a solid dosage pharmaceutical composition for oral administration, 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 anhydrous dextrose, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, anhydrous lactose, lactose monohydrate, maltitol, xylitol, sucrose, sucrose 97% + maltodextrin 3%, β-cyclodextrin, D-raffinose pentahydrate, D-melezitose monohydrate and microcrystalline cellulose, wherein the composition shows that at least 60% of the bendamustine is dissolved within 10 minutes, at least 70% is dissolved within 20 minutes, and at least 80% is dissolved within 30 minutes.

Particularly preferred sugars are mannitol, maltitol, erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose, trehalose, lactitol and 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 present invention also includes a combination of two or more sugars within the range of the above sugars.

A person skilled in the art is fully capable of selecting a suitable combination among the above-mentioned sugar excipients and obtaining a composition showing the following bendamustine dissolution behavior: at least 60% of bendamustine is dissolved within 20 minutes, at least 70% is dissolved within 40 minutes, and at least 80% is dissolved within 60 minutes, as measured in 500 ml of dissolution medium at a pH of 1.5 according to the European Pharmacopoeia using a paddle apparatus at a rotation speed of 50 rpm.

In a preferred embodiment, the composition is in the form of tablets, granules, or pills.

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

The most commonly used 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, 3rd edition, 1986). In order to prepare tablets with a uniform content of active ingredient, the mixture to be compressed must have both good flowability and good compressibility. It is not always possible to obtain good flowability by adding appropriate excipients (e.g., lubricants, anti-adhesives, and flow promoters) to the mixture. Therefore, the mixture is often granulated before compression molding.

Granulation is the process of forming a powdered mixture into approximately spherical or regularly shaped aggregates (called granules). This process can be achieved by dry granulation and wet granulation. Granulation is also used to convert powder mixtures with low cohesion into aggregates that, when compressed into tablets, 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 "granule" refers to an aggregate of particles, sometimes also referred to as granules. Granules are typically prepared by compaction and/or compression molding techniques (dry granulation), or by wet granulation using a liquid in which a wet granulation binder is optionally dissolved (Remington's Pharmaceutical Sciences, 18th ed., 1990, p. 1641). Wet granulation techniques also include extrusion techniques. The term granule therefore also includes pellets, spheres, and extrudates, with pellets being a preferred example of a granule.

Pellets can be described as small particles of a certain density and approximately 1.0 to 1.6 mm in diameter, which are produced by the pharmaceutical process of extrusion spheronization of a powdered mixture.

The active ingredient (optionally mixed with one or more excipients) may advantageously be provided with a coating in order 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.

Pellets are small, round solid dosage forms made by adding the active ingredient to a fluffy triglyceride mixture, which is rolled into a long string that is then cut into segments and rolled (J.T. Carstensen, Pharmaceutical principles of solid dosage forms, Technomic Publishing Company, 1993, p. 63).

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

The dosage form according to the present invention preferably has a coating. The coating serves various purposes: it can mask the taste of the active ingredient used in the composition while protecting the active ingredient from potential harmful effects caused by light and/or moisture, such as oxidation and degradation. Furthermore, the coating can protect the oral mucosa of the subject from damage caused by the active ingredient.

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

The expression "pharmaceutically acceptable esters thereof" refers to any pharmaceutically acceptable ester of bendamustine, such as esters of bendamustine with alkyl alcohols and esters of bendamustine with sugar alcohols. Examples of alkyl alcohols are C1-6 alkyl 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 ester, isopropyl ester, mannitol ester, and sorbitol ester, with bendamustine ethyl ester being most preferred.

The expression "a 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, it should be understood that non-pharmaceutically acceptable salts are also included within the scope of the present invention, as these compounds can be used to prepare pharmaceutically acceptable salts. For example, pharmaceutically acceptable salts of bendamustine are synthesized from corresponding compounds containing acid or basic groups by conventional chemical methods. Typically, these salts are 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 an organic solvent, or a mixture of the two. Non-aqueous media such as ether, ethyl acetate, isopropanol or acetonitrile are generally preferred. Examples of acids that can be used to form 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 can be derived from inorganic or organic bases to produce ammonium salts, alkali metal salts (lithium, sodium, potassium, etc.), alkaline earth metal salts such as calcium or magnesium, aluminum salts, lower alkylamine salts such as methylamine salts or ethylamine salts, lower alkyldiamine salts such as ethylenediamine salts, ethanolamine salts, N,N-dialkyleneethanolamine salts, triethanolamine salts, and glucosamine salts, as well as basic salts of amino acids. Acid salts prepared from hydrochloric acid, hydrobromic acid, and hydroiodic acid are particularly preferred, and hydrochloride is the most preferred pharmaceutically acceptable salt of bendamustine. The pharmaceutically acceptable salts are prepared by conventional techniques 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 formed with an alcohol (such as methanol, ethanol, propanol or isopropanol), a solvate formed with an ester (such as ethyl acetate), a solvate formed with an ether (such as methyl ether, ethyl ether or THF (tetrahydrofuran)), or a solvate formed with DMF (dimethylformamide), of which hydrates or solvates formed with alcohols (such as ethanol) are more preferred. The solvent constituting the solvate is preferably a pharmaceutically acceptable solvent.

Particularly preferably, 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 dosage of the active ingredient in the pharmaceutical composition can be easily determined by a technician according to the patient's condition, sex, weight, body surface area or age, especially determined according to the patient's weight and body surface area, and the range of the dosage is 10mg to 1000mg. Preferably, the daily dose of the active ingredient is about 50mg to about 1000mg, preferably about 100mg to about 500mg. The daily dose can be administered in a single dose or in multiple doses, for example twice or three times a day, most preferably in a single daily dose. The daily dose can be administered once a week or several times a week. The dosage form can include the amount of a single daily dose or a portion thereof. Preferably, the dosage form of the present invention includes about 10mg to about 1000mg, preferably about 25mg to about 600mg, more preferably about 50mg to about 200mg, and most preferably about 100mg of active ingredient.

Sugars are present in large quantities in the compositions of the present invention, preferably in amounts ranging from 2 to 5 times the weight of the active substance. When introduced into the compositions of the present invention, sugars have been shown to have a positive effect on the stability of the active compound. Furthermore, it has been unexpectedly found that these excipients increase the bioavailability of the active compound, particularly bendamustine hydrochloride, compared to reference capsules.

Preferable 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 contain 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 tablet press parts (hopper, die, and punch), reducing friction between particles, making it easier for tablets to be discharged from the die, and improving the flow rate of the mixture (to be compressed). The lubricant is generally selected from the group consisting of stearic acid, stearates or stearic acid esters, 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, stearyl palmitin, and sodium stearyl fumarate, and mixtures thereof. Stearic acid is the best choice.

In the present application, the term glidant is understood to be a substance that improves the flow properties of the mixture to be tableted. As glidant, any suitable glidant can be used, such as talc, silicon dioxide and silica starch and calcium silicate. Silicon dioxide is commonly used.

Typically, the term filler (or diluent) represents those excipients that are used to increase the volume of the material to be compressed. This increase in size improves the handling of the solid composition. If the dosage of the drug in each solid composition is low, or the solid composition is too little, then a filler is generally necessary. Examples of suitable fillers are lactose, sucrose, mannitol, sorbitol, saccharose, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen 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 binding agent is used to give pharmaceutical preparation cohesiveness, and this cohesiveness guarantees that described composition keeps intact (especially the tablet after compression molding).Different binding agents are used according to employed compaction technology (direct compression, dry granulation or wet granulation).For dry compaction technology (direct compression and dry granulation), suitable binding agent is lactose, sucrose, mannitol, sorbitol, sucrose, starch, pregelatinized starch, microcrystalline cellulose, powdered cellulose, calcium hydrogen phosphate, calcium carbonate and their combination in any.In a preferred embodiment, described binding agent is selected from the group consisting of lactose, starch, microcrystalline cellulose, microfine cellulose and their combination in any, most preferably anhydrous lactose and microcrystalline cellulose.In wet granulation process, binding agent both can be used as solution, also can be used in dry form.As suitable binding agent, can mention here (for example) polyvinyl pyrrolidone, dispersible cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, starch, pregelatinized starch, part pregelatinized starch, gum arabic, dextrin, amylopectin etc. Among these binders, dispersible cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are more preferred.

Pharmaceutical compositions, especially tablet compositions, may contain disintegrants to facilitate tablet decomposition or disintegration upon contact with aqueous physiological fluids. Disintegrants are generally responsible for rapidly disintegrating the tablet upon contact with body fluids (e.g., saliva, gastric juice, and intestinal fluids) when the tablet is swallowed. Substances used as disintegrants have been classified according to their chemical properties into starches, celluloses, cross-linked polymers, and the like. Studies have been conducted on the types and amounts of disintegrants used in the practice of the present invention, and it has been found that starch, modified starches (e.g., sodium starch glycolate), sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (cross-linked polyvinyl pyrrolidone), polacrilin potassium (IRP88), and low-substituted hydroxypropyl cellulose can produce excellent disintegration effects.

The stability of aqueous solutions of bendamustine is strongly affected by pH. Extensive hydrolysis of the compound is observed at pH values greater than about 5. Decomposition proceeds rapidly at pH values > 5 and the resulting by-product content is high within this pH range. 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 (HP3):

Orally administered drugs are typically absorbed in the stomach, small intestine, and/or large intestine. The pH in the stomach is approximately 1 to 3.5, in the small intestine approximately 6.5 to 7.6, and in the large intestine approximately 7.5 to 8.0. Therefore, for compounds such as bendamustine that tend to degrade in aqueous environments above a pH of 5, it is highly preferred that they be absorbed in the stomach and not excreted into the small intestine, or even the large intestine, to avoid degradation. Therefore, there is a need for pharmaceutical compositions in which bendamustine is completely or at least largely absorbed in the stomach, thereby avoiding or reducing degradation of bendamustine in the small intestine or the large intestine.

The applicant has surprisingly found that the above-mentioned problem can be solved by using the pharmaceutical compositions of the present invention, in particular pharmaceutical compositions containing the above-mentioned preferred carbohydrates. These compositions containing bendamustine exhibit a rapid dissolution behavior, in particular such a dissolution behavior of bendamustine that, as measured in artificial gastric fluid according to the European Pharmacopoeia using a paddle apparatus at a speed of 50 rpm, at least 60% of the bendamustine is dissolved within 20 minutes, preferably within 10 minutes, at least 70% within 40 minutes, preferably within 20 minutes, and at least 80% within 60 minutes, preferably within 30 minutes, and most preferably at least 75% within 10 minutes, at least 85% within 20 minutes, and at least 90% within 30 minutes. Artificial gastric fluid as used herein refers to a solution prepared by dissolving 2 g of sodium chloride in 1000 ml of water and then adjusting the pH to 1.5 ± 0.05 with 5N hydrochloric acid.

The total time it takes for the drug to be eliminated from the stomach to the small intestine is between about 20 minutes and 5 hours, typically between about 30 minutes and 3 hours. Therefore, the pharmaceutical composition of the present invention advantageously reduces the degradation of bendamustine in the patient's body because the bendamustine therein is largely released and dissolved in the stomach, thereby improving the bioavailability of the composition of the present invention comprising bendamustine.

In another aspect of the present invention, the solid dosage pharmaceutical composition can be used for treatment, induction, salvage therapy, pre-stem cell transplantation conditioning, maintenance therapy, or treatment of residual disease in a human or animal (preferably a human) medical condition selected from chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid 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 present invention also includes a method for treating a medical condition in a human or animal body, comprising administering to a human or animal body in need of treatment an effective amount of a pharmaceutical formulation of the present invention, wherein the medical condition is selected from the group consisting of chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, and an autoimmune disease. A preferred medical condition is non-Hodgkin's lymphoma.

In another aspect of the present invention, the pharmaceutical composition can be administered in combination with at least one other active agent, wherein the other active agent is administered before, simultaneously with, or after the administration of the pharmaceutical composition. The at least one other active agent is preferably a CD20-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), dapoline (FK866), YM155, thalidomide and its analogs (e.g., thalidomide or lenalidomide), or a proteasome inhibitor (e.g., bortezomib).

The pharmaceutical composition of the present invention can also be administered in combination with at least one corticosteroid, wherein the corticosteroid is administered before, simultaneously with, or after the administration of the pharmaceutical composition. Examples of the corticosteroid are prednisone, prednisolone, and dexamethasone.

The present invention will be further described 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 considered as limiting the present invention.

example

1. Compatibility test

Example 1a

A compatibility test mixture was prepared containing bendamustine hydrochloride and excipients in a 1:1 (mass/mass) ratio. The excipients were selected from mannitol and lactose. Following preparation, the mixture was placed in clear glass Agilent HPLC vials (6 ml) and stored under the various storage conditions shown in Table 1 below. At defined time points, samples were removed from the storage conditions and tested for purity (HPLC, column: Zorbax Bonus-RP, 5 μm; column oven temperature: 30°C; autosampler temperature: 5°C; detector: 254 nm) and appearance.

Table 1: Storage conditions

*Store at 50℃ for one month before storing at 70℃

**Store at 25℃/60% r.h. for one month before storing at 40℃/75%

In all these mixtures, the content of bendamustine hydrochloride (measured by HPLC) remained almost unchanged and remained above 99% for all three storage conditions. The hydrolysis product HP1 was hardly detected for all three storage conditions (area % <0.2).

The bendamustine hydrochloride mixtures were visually inspected. All tested mixtures met specifications and appeared as white to off-white powders when tested immediately after preparation and after one month under all three storage conditions.

Example 1b

To further perform compatibility testing according to the method of Example 1a, a mixture containing bendamustine hydrochloride and excipients in a 1:1 (mass/mass) ratio was prepared. The excipients were selected from EPO, sodium carboxymethylcellulose (RC 591), and cross-linked polyvinyl pyrrolidone (Crospovidone).

When EPO was used, the initial levels of the impurities HP1 (hydrolysis product) and BM1 dimer increased significantly (HP1: 1.5%, BM1 dimer: 1%), but a decrease in these impurities during storage was detected under all storage conditions, excluding the effects of humidity. When cross-linked polyvinyl pyrrolidone was used, a significant increase in HP1 from 0.1% to 0.4% was detected under storage conditions of 40°C/75% RH/open vial. No increase in HP1 was detected under all other storage conditions (closed vials).

Under storage conditions of 70°C/closed vials, the appearance of the mixture containing EPO and the mixture containing cross-linked polyvinyl pyrrolidone changed. Both mixtures became slightly viscous. In addition, the color of the mixture containing cross-linked polyvinyl pyrrolidone changed from white to cream.

Under the storage condition of 70°C/closed vials, the colors of the mixture containing and the mixture containing RC591 also changed to cream color.

2. Tablet preparation

Example 2

253 g of a mixture containing mannitol (as the main excipient) and microcrystalline cellulose, colloidal silicon dioxide, talc, and stearic acid in the relative amounts shown in Table 2a below was prepared by mixing in a 1 liter cube blender (Erweka) for 15 minutes. 10.612 g of the mixture and 3.0 g of bendamustine hydrochloride were then sieved through a 0.425 mm sieve and subsequently transferred to a Turbula mixer T2A equipped with a 50 ml glass vial and then mixed at 60 rpm for 10 minutes.

The resulting mixture is compressed into round tablets having the following characteristics:

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

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

*1: NP1: 4-[6-(2-chloroethyl)-3,6,7,8-tetrahydro-3-methyl-imidazo[4,5-h]-[1,4]benzothiazin-2-yl]butanoic acid

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

BM1EE: 4-[5-[Bis(2-chloroethyl)amino]-1-methyl-benzimidazol-2-yl]butanoic acid ethyl ester

*2: n.d.: Unable to detect, 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°C/75% RH (glass vials opened) or at 50°C (glass vials closed). The content of bendamustine hydrochloride and related substances was measured by HPLC as described above. The results are shown in Table 3b:

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°C/75% RH (glass vials opened) or at 50°C (glass vials closed). The amounts of bendamustine hydrochloride and related substances were measured by HPLC as described above. The results are shown in Table 4b:

Prior art reference examples

20.0 ± 1 mg of bendamustine hydrochloride was weighed and placed into the capsule body of an empty hard gelatin capsule, which was then placed into a clear glass Agilent HPLC vial (6 ml). The capsule was sealed by placing the capsule cap on the capsule body and gently pressing. The capsules were stored at 40°C/75% RH (glass vial open) or 50°C (glass vial closed). As described above, the amount of bendamustine hydrochloride and related substances was measured by HPLC. The results are shown in Table 5:

It is apparent that, despite being prepared from pure bendamustine hydrochloride without any further processing steps, the capsule formulation exhibits significantly less stability than the tablet formulation of the present invention. Significant degradation products were formed within one month of storage at both 40°C/75% RH (open glass vial) and 50°C (closed glass vial). After one month of storage at 40°C and 75% RH (relative humidity) with the vial open, the amount of the hydrolysis product HP1 increased fourfold. HP1 levels were even higher in the closed vial, likely due to a reaction with the capsule. Overall, tablets provide a much more stable solid dosage form than capsules.

Example 5

8.0 g of hydroxypropyl methylcellulose and 1.5 g of PEG 6000 were dissolved in 88.5 g of purified water. 2.0 g of yellow ferric oxide and 0.5 g of titanium oxide were then dispersed to form a coating solution. The tablets obtained in Example 2 were coated with this solution using a film coater at a concentration of 3% per tablet.

Example 6

Preparation method of 1000 tablets

All tablet ingredients except colloidal silicon dioxide and stearic acid are loaded into a Somakon container (5 L). Bendamustine is added and mixed at 1000 rpm for 4 minutes (wiper 10 rpm). The resulting mixture is sieved through a 0.5 mm screen. The mixture is reloaded into the container and colloidal silicon dioxide is added. Mix under the above conditions for 2 minutes. Stearic acid is then added and mixing is continued for 1 minute. The mixture is subsequently sieved through a 0.5 mm screen, reloaded into the container and mixed for another 30 seconds, with mixing conditions all being the same as above.

The mixture was compressed into round tablets having the following characteristics:

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

The tablets were then film-coated with the dispersion to a mass gain of 5%.

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

The core tablets and film-coated tablets were stored in sealed amber glass vials at 40°C/75% RH. The amounts of bendamustine hydrochloride and related substances such as degradation products and synthetic by-products were measured by HPLC as described above. The results are shown in Tables 6b.1 and 6b.2.

*3: Unidentified compound peak at a relative retention time of 0.69 relative to the main peak

Example 7

Preparation method of 1000 tablets

All tablet ingredients except colloidal silicon dioxide and stearic acid are loaded into a Somakon container (5 L). Bendamustine is added and mixed at 1000 rpm for 4 minutes (wiper 10 rpm). The resulting mixture is sieved through a 0.5 mm screen. The mixture is reloaded into the container and colloidal silicon dioxide is added. Mix under the above conditions for 2 minutes. Stearic acid is then added and mixing is continued for 1 minute. The mixture is subsequently sieved through a 0.5 mm screen, reloaded into the container and mixed for another 30 seconds, with mixing conditions all being the same as above.

The mixture was compressed into round tablets having the following characteristics:

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

The tablets were then film-coated with the dispersion until a mass gain of 3%.

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

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

Example 8

Preparation method of 1000 tablets

All tablet ingredients except colloidal silicon dioxide and stearic acid are loaded into a Somakon container (2.5 L). Bendamustine is added and mixed at 1000 rpm for 4 minutes (wiper 10 rpm). The resulting mixture is sieved through a 0.5 mm screen. The mixture is reloaded into the container and colloidal silicon dioxide is added. Mix under the above conditions for 2 minutes. Stearic acid is then added and mixing is continued for 1 minute. The mixture is subsequently sieved through a 0.5 mm screen, reloaded into the container and mixed for another 30 seconds, with mixing conditions all being the same as above.

The mixture was compressed into round tablets having the following characteristics:

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

The tablets were then film-coated with the dispersion until a mass gain of 3%.

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

The core tablets and film-coated tablets were stored in sealed amber glass vials at 40°C/75% RH. The amounts of bendamustine hydrochloride and related substances were measured by HPLC as described above. The results are shown in Tables 8b.1 and 8b.2:

Example 9

Preparation of 600 tablets of formulation PF1:

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

The core tablets were then coated with a 9% aqueous suspension of Opadry™ White in a coating pan (4M8 ForMate PanCoat) and dried. The average tablet mass was 342.42 mg. The tablets were then packaged in amber glass bottles sealed with screw caps and stored at 40°C/75% RH.

Preparation of 600 tablets of formulation PF2:

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

The core tablets were then coated with a 9% aqueous suspension of TM White in a coating pan (4M8 ForMate PanCoat) and dried. The average tablet mass was 340.1 mg. The tablets were then packaged in amber glass bottles sealed with screw caps and stored at 40°C/75% RH.

Preparation method of preparation PF3:

Sorbitol and anhydrous dextrose were weighed. 140.64 g of sorbitol was dissolved in 105.48 g of purified water, and the resulting solution was then used to granulate 659.36 g of dextrose in a fluidized bed granulator (4M8 ForMate FluidBed). The granules were then dried at 60°C and sieved through an 850 μm mesh.

33.06 g of bendamustine hydrochloride, 149.82 g of sorbitol/dextrose granules, 13.8 g of microcrystalline cellulose, and 1.32 g of magnesium stearate were weighed and transferred to a double polyethylene bag and mixed for 5 minutes. The powder mixture was then transferred to the hopper of an eccentric tablet press (Korsch EKO) and compressed into round tablets with an average diameter of 10.0 mm. The average tablet mass ranged from 335.99 mg (starting) to 339.50 mg (final); the friability was 0%; and the average hardness values ranged from 125.60 N (starting) to 129.7 N (final). The tablets then underwent a two-step preconditioning process (performed only on selected batches): the tablets were conditioned at 25°C/60% RH for two hours, followed by 40°C for two hours.

The tablets were then coated with a 9% aqueous suspension of TM White in a coating pan (4M8 ForMate PanCoat). The average mass of the tablets was 341.43 mg. The tablets were then packed into amber glass bottles sealed with screw caps and stored at 40°C/75% RH.

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

3. Dissolution test

Example 10

At T = 0, the tablet formulations of Examples 2 and 3 were subjected to a dissolution test in artificial gastric fluid. The dissolution samples were tested for analysis by HPLC (column: Zorbax Bonus-RP, 5 μm; column oven temperature: 30°C; autosampler temperature: 5°C; detector: 254 nm). Artificial gastric fluid (pH 1.5) was prepared by the following steps: 2 g of sodium chloride p.A. was dissolved in 1000 ml of water and the pH was adjusted to 1.5 ± 0.05 with 5N hydrochloric acid. The dissolution test was performed using Apparatus 2 (paddle apparatus) according to Chapter 2.9.3 of the European Pharmacopoeia 6.0. The paddle speed was 50 rpm, the temperature was 37°C ± 0.5°C, 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 10a:

The results of the same dissolution test conducted on the coated tablet formulations of Examples 6, 7 and 8 at T=0 are shown in Table 10b below:

Table 10b

The corresponding dissolution data of the tablets of Example 9 are:

As can be seen from the above, all tablet formulations of the present invention exhibit a rapid dissolution behavior of bendamustine. Specifically, the formulations of the present invention exhibit a dissolution behavior of bendamustine as defined herein before.

4. In vivo testing

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

Research Experiment 1

The study objectives were to determine the bioavailability of a single dose (i.e., 50 mg) of bendamustine in three tablet formulations (T1-3) and one capsule formulation (C) (a total of four oral formulations): AUC and Cmax

Total number of animals required: 16

Basic design:

Crossover design, 8 animals per arm:

Table 11a: Phase 1 (single dose tablet or capsule, day 1):

One week wash-out

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

One week washout

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

Research Experiment 2

The study objectives were to determine the bioavailability of a dose (i.e., 50 mg) of bendamustine in one tablet formulation (T4) and one capsule formulation (C) (total of three oral formulations): AUC and Cmax

Total number of animals required: 16

Basic design:

Crossover design, 8 animals per arm:

Table 12a: Phase 1 (single dose capsule, day 1)

One week washout

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

Example 11

The coated tablets of Example 9 (Formulation 3, with coating, Tablet T4) containing 50 mg of bendamustine were orally administered to male and female dogs and compared with the capsules of the reference example.

The mean plasma concentrations of the capsule formulation and the coated tablets of Example 9 over time are shown in FIG1 .

Example 12

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

The mean plasma-time relationships for the capsule formulations and the coated tablets of Examples 6-8 are shown in FIG1 .

Experiments were conducted to:

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

-Evaluate the compatibility between API and excipients;

- Placebo batches and API-containing batches were developed by studying different manufacturing processes: dry granulation, direct compression, and wet granulation;

- Evaluate different bendamustine hydrochloride/sugar weight ratios;

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

-Study the effect of moisture content on the technical properties and stability of the prepared tablets;

- Tablets were prepared using a commercially available lyophilized bendamustine hydrochloride product and the properties of these tablets were compared with those of tablets prepared using equivalent amounts of mannitol and bendamustine hydrochloride.

The following sugars were used to prepare tablets of the present invention, which contained 50 mg of bendamustine (55 mg for bendamustine hydrochloride).

Table 13

The quality of the prepared batches was assessed by observation of physical appearance, identity testing (HPLC), dissolution testing, assay and related substances analysis (HPLC), content uniformity testing (HPLC), hardness testing, and water content (Karl Fischer method). The batches were packaged in amber glass bottles and subjected to accelerated stability studies under the storage conditions detailed in the table below. For each prepared batch containing the API, some tablets were stored at 5°C as backup samples.

Next, various excipients were investigated in relation to the tablet manufacturing process. Several placebo preparation trials were carried out using these excipients using dry granulation to obtain preliminary information on the manufacturing process suitable for obtaining tablets of good quality.

Two types of disintegrants were used: microcrystalline cellulose (pH 112) as the standard disintegrant, and cross-linked polyvinyl pyrrolidone was used only for batch D001T/002. This was chosen based on the similarity between this formulation and the prototype formulation of Example 9. Magnesium stearate was used as a lubricant for all prepared batches. The dry granulation preparation process for the placebo trial included the following steps:

1. Sugar and a partial amount of lubricant (83.3% _w/w of the total amount) were accurately weighed, followed by mixing in a polyethylene bag for 2 minutes.

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

3. The resulting slug was sieved using an 850 micron screen.

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

The composition of each placebo formulation and the results of the analytical tests performed on the final blend and tablets are summarized in Tables 14 and 15. Results observed during the preparation of the placebo batches and/or during their analytical characterization are shown in Table 16.

Analytical and physical test results for placebo batches D001T/001, D001T/002, D001T/004, D001T/013, and D001T/015 showed that these formulations were suitable for preparation by dry granulation and for further studies with the addition of the API. All other formulations were characterized by difficult powder compaction and, when tablets were obtained, high friability.

Batch D001T/005 (filler: β-cyclodextrin) showed good behavior during dry preparation, high hardness, low friability, but long disintegration time. This formulation was further investigated by using a superdisintegrant and adding the API (see below).

The batch was prepared by dry granulation with a bendamustine hydrochloride/sugar weight ratio of 1:5.

A placebo formulation assessed as more suitable for preparation of tablets containing an active pharmaceutical ingredient (API) by dry granulation was changed to contain the API, and two API/sugar weight ratios were explored: 1:5 and 1:2.

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

Two types of disintegrants were used: microcrystalline cellulose (PH 112) as standard disintegrant, and cross-linked polyvinyl pyrrolidone used only for batch D001T/022. Magnesium stearate was used as lubricant for all batches prepared.

The process for preparing API-containing batches using dry granulation involves 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 polyethylene bag for 5 minutes.

2. Compress the powder mixture using a tablet press equipped with 18 mm diameter punches.

3. The resulting billet was sieved using an 850 μm sieve to obtain granules.

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

5. The resulting mixture was compressed into tablets using a 10 mm diameter punch.

Table 17 summarizes the composition of each API-containing formulation prepared, as well as the results of analytical tests performed on the final mixture containing the API; Table 18 summarizes the results of analytical tests performed on the resulting preparations.

Table 17. Dry granulation - API/sugar weight ratio 1:5. Composition and analytical results of the final blend containing the API batch.

Table 18. Dry Granulation - API/Sugar Weight Ratio 1:5. Analytical Results of Tablets from API-Containing Batches.

The results of analytical testing of the final blend and the resulting preparations (primarily content uniformity and purity) were generally favorable. All API-containing batches showed satisfactory quality uniformity, API content uniformity, and low impurity levels. The impurity profiles of all preparations met the API specifications (see specification limits in the table), indicating that no degradation occurred during the manufacturing process.

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

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

All sugars previously studied using dry granulation to prepare 1:5 weight ratio API/sugar tablets were evaluated again at a 1:2 ratio.

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

Two types of disintegrants were used: microcrystalline cellulose (PH 112) as the standard disintegrant and cross-linked polyvinyl pyrrolidone (CPPP) for batch D001T/105 only. For this batch, the use of PH 112 and CPPP were explored. The choice was based on a cyclodextrin-based formulation previously prepared by dry granulation at an API/sugar ratio of 1:5 (see previous results).

Tables 19 and 20 summarize the composition of each API-containing formulation prepared by dry granulation at an API/sugar weight ratio of 1:2, as well as the results of analytical testing of the final blends and tablets. All API-containing batches demonstrated suitable mass uniformity, API content uniformity, and low impurity levels. In most cases, friability and hardness values met specifications. In the case of batches D001T/093, D001T/095, and D001T/096, the results of dissolution testing on six tablets were outside the specification values with high RSDs, and the testing was extended to a sample of 12 tablets.

The cyclodextrin-based tablets showed good properties with both disintegrants (PH 112 and ).

Table 19. Dry Granulation - API/Sugar Weight Ratio 1:2. Composition and analytical results of the final blend containing the API batch.

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

Sugars with characteristics suitable for preparation by dry granulation were investigated using direct compression to develop tablets with an API/sugar ratio of 1:5.

Two types of disintegrants were used: microcrystalline cellulose (PH 112) as the standard disintegrant, and cross-linked polyvinyl pyrrolidone used only for batch D001T/029.

This preparation process includes the following steps:

1. Weigh the API and excipients.

2. The raw materials were transferred to a double polyethylene bag and mixed for about 5 minutes until a uniform powdery mixture was obtained.

3. Transfer the powdered mixture into the tablet press hopper.

4. The powdered mixture was compressed into tablets using an eccentric tablet press equipped with 10 mm diameter punches.

Characteristics of 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 Final Blends Containing API Batches.

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

Table 22. Analytical results of tablets from direct compression - API/sugar weight ratio 1:5 containing API batch.

As shown in the table above, with the exception of batch D001T/030 (filler: sucrose 97% + maltodextrin 3%) which showed non-uniform API content and slightly increased friability values, the API-containing tablets prepared by direct compression did not show any key differences from the tablets prepared by dry granulation.

Wet granulation:

Placebo exploratory trials

Based on the results obtained in Parts 1 and 2 of the protocol, wet granulation studies were conducted on sugars that were not suitable for dry granulation or direct compression.

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

Each sugar was granulated according to the steps described in the flow chart of Figure 2. At the end of each step, the moist granulated sugar was dried and subjected to compression molding tests to evaluate the suitability of the granules for tableting. Placebo batches were prepared only for granulated sugars with questionable compression molding test results. The composition of the placebo test and the relevant analytical results are shown in Table 23.

The placebo batch was prepared according to the following steps:

1. Use a fluidized bed or high shear granulator to wet granulate the sugar with water or sorbitol solution (see the flow chart and Table 23 for the wet granulation preparation test above).

2. Dry the moist granulated sugar 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 corresponding formulation were weighed and mixed in a polyethylene bag for 2 minutes.

5. The powdered mixture was compressed into tablets using an eccentric tablet press equipped with 10 mm diameter punches.

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

API-containing batches prepared by wet granulation at an API/sugar weight ratio of 1:5

All sugars that appeared unsuitable for tablet preparation by dry granulation or direct compression techniques were subjected to preparative trials involving wet granulation processes.

The preparation steps for these bench-scale experiments are summarized below:

1. Use a fluidized bed or high shear granulator to wet granulate the sugar with water or sorbitol solution (see the flow chart and Table 24 for the wet granulation preparation test above).

2. Dry the moist granulated sugar in a fluid bed granulator or in an oven.

3. Sieve through 850 micron and 710 micron sieves.

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

5. The powdered mixture was compressed into tablets using an eccentric tablet press equipped with 10 mm diameter punches.

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

Tables 24 and 25 list the composition of each API-containing formulation prepared by wet granulation, as well as the results of analytical tests performed on the final blends and tablets.

In most cases, analytical testing of the final blend and finished product met specifications. No degradation occurred during the manufacturing process.

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

Batches D001T/060, D001T/061, D001T/082, and D001T/086 had low values in the API analysis, while batches D001T/082 and D001T/086 failed content uniformity despite sieving the granules using 850 and 710 micron sieves, respectively. This result may be attributed to poor powder mixing.

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

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

At a 1:2 ratio, fructose was not evaluated because the resulting granules were not suitable for tableting.

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

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

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

2. Prepare a mixture containing the API.

3. The mixture is dry granulated (blank preparation→blank screening).

4. The resulting mixture was compressed using 8 mm diameter punches.

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

Tables 26 and 27 show the composition and analytical results of API-containing batches prepared using wet-granulated sugar at an API/sugar weight ratio of 1:2. In most cases, friability exceeded specifications. The API/sugar weight variation did not compromise the technical performance of batch D001T/084 (filler: granulated mannitol).

Effect of API/mannitol weight ratio

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

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

For ratios of 1:0.01, 1:0.1 and 1:0.5, we adopted the above reported preparation process (wet granulation of sugar followed by dry granulation) to improve API content uniformity. The resulting blends were tableted using 6 mm diameter punches.

The following tables (Tables 28 and 29) summarize the composition and analytical results of API-containing formulations prepared to investigate the effects of varying API/mannitol ratios. Batches D001T/111, D001T/083, and D001T/106 exhibited high friability, while batches D001T/106, D001T/108, and D001T/109 failed to meet content uniformity standards, deviating from previously observed data trends. This result may be attributed to the fact that these batches were prepared using a novel bendamustine hydrochloride (Cat. No. F08-05873) formulation that may have different physical properties.

Carbohydrate combination research

Tables 30 and 31 show the results of the carbohydrate combination studies.

The following combinations were studied:

-Monosaccharide/disaccharide 1:1

( ^* ) Mannitol (Pearlitol 200SD)/Anhydrous Lactose (SuperTab 21AN)

Sorbitol (Neosorb P60W)/Maltose (Sunmalt S)

- Oligosaccharides/monosaccharides 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)

β-Cyclodextrin (Kleptose DC)/Sucrose (EV Saccharide)

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

The manufacturing process involves direct compression of raw or granulated sugar.

These batches were prepared using Avicel PH 112 and magnesium stearate as disintegrant and lubricant, respectively, by the following steps:

1. Accurately weigh the sugar (or granulated sugar), bendamustine hydrochloride and excipients and mix them in a double polyethylene bag for 5 minutes.

2. The resulting mixture was compressed into tablets using a 10 mm diameter punch.

Table 30. Carbohydrate combination study. Composition and analytical results of the final mixture containing API batches.

Tablets prepared for the studied saccharide combinations generally showed good properties. However, batch D001T/102 (raffinose pentahydrate/mannitol (Pearlitol 200SD)) showed high friability, while batches D001T/100 and D001T/049 had heterogeneous API content.

Example 14. Lyophilized Bendamustine Hydrochloride and Bendamustine Hydrochloride/Mannitol Tablets (The weight ratio of API/sugar is 1:1.2)

Tablets containing bendamustine hydrochloride/mannitol at a weight ratio of 1:1.2 were prepared using a lyophilizate obtained from a commercially available intravenous preparation or using wet granulated mannitol and bendamustine hydrochloride.

Preparation was performed according to the following experimental procedure: freeze-dried powder was taken out from a vial and sieved using a mesh of 850 microns. Accurately weigh the resulting powder and lubricant (magnesium stearate) and mixed them in a polyethylene bag for 5 minutes. The mixture was slowly transferred to the compression chamber of a tablet press and manually compressed using an 8 mm diameter punch to obtain a small blank. The blank was sieved using a mesh of 850 microns and the resulting granules were manually compressed using an 8 mm diameter punch.

The same operating procedures as described above in this example were used to prepare bendamustine hydrochloride/mannitol tablets.

The composition of the formulation is shown in Table 32.

Table 32. Composition of the final blend of Ribomustin and Bendamustine/Mannitol Tablets containing API.

(*) Equivalent to 45.16% bendamustine hydrochloride and 54.20% mannitol

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

Table 33. Analytical results of Ribomustin and Bendamustine/Mannitol tablets. Tablets containing API batches

Using the impurity profile of the bendamustine hydrochloride API as a reference indicator (see specification limits in the table), batch D001T/125 exhibited impurity HP1 exceeding the specification value. Dissolution testing results highlighted that, while the dissolution behavior of tablets containing the lyophilized bendamustine hydrochloride/mannitol mixture was faster after 10 minutes, after 30 minutes, both formulations met the current specification. Batch D001T/126 exhibited friability exceeding the specification, while batch D001T/125 was not tested due to a lack of sufficient material.

Industrial Applications

The pharmaceutical composition of the present invention exhibits numerous advantages. Patients can easily use the pharmaceutical composition without the assistance of a supervising medical staff. Therefore, the time-consuming process of being transported to a hospital may no longer be necessary, thereby improving patient compliance.

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

By adopting the dosage form of the present invention, the volume of the dosage form can be significantly reduced. The size reduction is beneficial from the perspective of production and handling as well as from the perspective of patient compliance.

The pharmaceutical composition exhibits a high in vitro dissolution rate, which reduces the degradation of bendamustine in vivo, thereby improving the in vivo bioavailability of bendamustine.

Claims (14)

1. An orally administered solid dosage form pharmaceutical composition comprising: bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable sugar excipient, the sugar excipient being a pharmaceutically acceptable sugar selected from one or more of lactose, sucrose, glucose, microcrystalline cellulose and 97% sucrose + 3% maltodextrin, wherein the weight ratio of the active ingredient to the sugar excipient is in the range of 1:1 to 1:5, characterized in that the pharmaceutical composition is in the form of tablets, granules or pills. 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the active ingredient to the glycosyl excipient is 1:2 to 1:5. 3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the tablet, the granule, or the pill has a coating. 4. The pharmaceutical composition according to any one of claims 1 to 2, wherein the active ingredient is bendamustine hydrochloride. 5. The pharmaceutical composition according to any one of claims 1 to 2, comprising 10 mg to 1000 mg of the active ingredient and 30 mg to 5000 mg of the glycosaminoglycan. 6. The pharmaceutical composition according to any one of claims 1 to 2, wherein the sugar excipient is selected from anhydrous lactose and lactose monohydrate. 7. The pharmaceutical composition according to any one of claims 1 to 2, further comprising a pharmaceutically acceptable lubricant, filler, and/or disintegrant. 8. The pharmaceutical composition according to claim 1, which exhibits the following dissolution behavior of bendamustine: measured according to the European Pharmacopoeia using a paddle apparatus at 50 rpm in 500 ml of dissolution medium at pH 1.5, the bendamustine dissolves by at least 60% within 10 minutes, at least 70% within 20 minutes, and at least 80% within 30 minutes. 9. The use of the pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for treating a medical condition selected from: chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid 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 diseases. 10. The application according to claim 9, wherein the pharmaceutical composition further comprises at least one other active agent. 11. The application according to claim 10, wherein the other active agent is a CD20-specific antibody, doxorubicin or daunorubicin, vinblastine or cisplatin or carboplatin. 12. The application according to claim 11, wherein the CD20-specific antibody is rituximab; and wherein the vincristine is vincristine. 13. The application according to any one of claims 9 to 12, wherein the pharmaceutical composition further comprises at least one corticosteroid. 14. The application according to claim 13, wherein the corticosteroid is prednisone or prednisolone.