KR20190015329A - A pharmaceutical composition of a dapagliflozin co-crystal - Google Patents

Abstract

The present invention relates to oral pharmaceutical compositions comprising multiparticulated citric acid co-crystals and one or more pharmaceutically acceptable excipients and processes for their preparation. The present invention also relates to a method of treating diabetes using these pharmaceutical compositions.

Description

A pharmaceutical composition of a dapagliflozin co-crystal

The present invention relates to oral pharmaceutical compositions comprising dapagliflozin citrate co-crystals and one or more pharmaceutically acceptable excipients and processes for their preparation. The present invention also relates to a method of treating diabetes using said pharmaceutical composition.

Dapagliflozin is chemically synthesized from (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4- ethoxybenzyl) phenyl] -6- (hydroxymethyl) tetrahydro- - < / RTI > pyran-3,4,5-triol. Currently commercially available formulations of Dapagliflozin contain the propanediol (propylene glycol) monohydrate solvate of the dapagliflozin as the active ingredient. Commercially available dapagliflozines are crystalline in nature. Conversely, the dapagliflozed base can exist in amorphous form.

U.S. Patent No. 6,515,117 reports compound dapagliflozin. U.S. Patent No. 7,919,598 reports (S) -propylene glycol solvates of dapagliflozin and their preparation processes.

U.S. Pat. Nos. 7,851,502, 8,221,786, and 8,361,972 report pharmaceutical compositions comprising a certain amount of polygalloglobulin or polygalloglobulin propylene glycol hydrate and certain excipients. U.S. Patent No. 8,221,786 also reports pharmaceutical compositions in the form of stock granulation comprising multiparticulate propylene glycol hydrates and excipients.

PCT Publication No. WO 2012/163546 reports pharmaceutical compositions comprising cyclodextrin and dapagliflozin, in some embodiments as inclusion compounds.

PCT Publication No. WO 2015/011113 reports pharmaceutical compositions comprising amorphous solids dispersions or adsorbates of polygalloflozin with one or more pharmaceutically acceptable excipients.

PCT Publication No. WO 2015/104658 reports polydomplexes in the amorphous form and solid dispersions containing them.

A new crystal of dapagliflozin containing citric acid is reported in PCT Publication No. WO 2015/198227, which is hereby incorporated by reference in its entirety. These co-crystals have been reported to have higher solubility, better storage stability, and better handling and processing capabilities due to non-hygroscopicity when compared to other polymorphic forms. These decisions have been reported to be useful in the treatment of diabetic patients.

The present invention is directed to oral pharmaceutical compositions comprising multiparticulated citric acid co-crystals and one or more pharmaceutically acceptable excipients. In some embodiments, the multipaggregated citric acid crystal is present in an amount from about 0.5% to about 25% by weight of the active moiety based on the total weight of the composition. In some embodiments, the oral pharmaceutical compositions of the present invention are prepared by a wet granulation process or by a dry process such as direct compression and dry granulation.

The present invention provides oral medicaments comprising a dapagliflozin citrate co-crystal, especially a solid oral dosage form, so that the therapeutic benefit of the dapagliflozin can be delivered to a patient in need thereof. In some embodiments, the invention provides stable oral pharmaceuticals that are easy to manufacture, provide acceptable uniformity, and provide a rapid dissolution profile. In some embodiments, the invention provides an oral pharmaceutical composition comprising multiparticulated citric acid co-crystals and one or more pharmaceutically acceptable excipients.

According to some embodiments, the polygallized citrate co-crystals comprise from about 0.5% to about 25%, from about 1% to about 20%, from about 2% to about 15% , From about 3 wt% to about 10 wt%, or from about 4 wt% to about 8 wt%. According to some embodiments, the polygallophyll citrate crystal is from about 0.5% to about 25% by weight of the total weight of the composition. In some embodiments, the multi-phaglypholated citrate crystal is from about 4% to about 8% by weight of the total weight of the composition. Unless otherwise stated, "% " and " percent " when referring to the amount of active agent or excipient (e.g., diluent, disintegrant, lubricant, glidant, etc.) Refers to the weight of the active agent or excipient relative to the weight of the composition.

According to some embodiments, the multi-phaglypholated citrate crystals comprise from about 1 mg to about 100 mg, from about 2 mg to about 75 mg, from about 3 mg to about 50 mg, from about 4 mg to about 40 mg, from about 5 mg to about 25 mg, for example, in a single dosage form. In some embodiments, the multipaggregated citrate co-crystals comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg , About 10 mg, about 12 mg, about 15 mg, about 20 mg, or about 25 mg. In some embodiments, the dapaglifloated citrate crystals are present in an effective amount in the pharmaceutical composition. As used herein, the term " effective amount " of an agent is an amount sufficient to result in beneficial or desired results, such as a clinical outcome, and thus an " effective amount "

In some embodiments, the pharmaceutically acceptable excipients are selected from one or more of diluents, binders, disintegrants, lubricants, and mixtures thereof. In some embodiments, the pharmaceutical compositions do not contain a binder.

In some embodiments, the disclosure of the present invention provides compositions with increased stability over time, increased stability at various temperatures, and / or increased stability at various humidity levels. For example, in some embodiments, the present invention can be used at a relative humidity ("RH") of 65% and at 3, 6, 9, 12, 15, Lt; / RTI > months. In some embodiments, the present invention provides compositions that are stable for 3 months, 6 months, 9 months, 12 months, 15 months, 18 months or 24 months when stored at 75% RH and 40 占 폚.

In some embodiments, the compositions are stable for 3 months when stored at 30 DEG C and 65% relative humidity (" RH "). In some embodiments, the compositions are stable for 3 months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 3 months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 3 months when stored at 40 < 0 > C and 75% RH and when stored at 40 < 0 > C and 75% RH.

In some embodiments, the compositions are stable for six months when stored at 30 DEG C and 65% relative humidity (" RH "). In some embodiments, the compositions are stable for six months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for six months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 6 months when stored at 40 < 0 > C and 75% RH and when stored at 40 < 0 > C and 75% RH.

In some embodiments, the compositions are stable for 9 months when stored at 30 DEG C and 65% relative humidity (" RH "). In some embodiments, the compositions are stable for 9 months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 9 months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 9 months when stored at 40 < 0 > C and 75% RH and when stored at 40 < 0 > C and 75% RH.

In some embodiments, the compositions are stable for 12 months when stored at 30 DEG C and 65% relative humidity (" RH "). In some embodiments, the compositions are stable for 12 months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 12 months when stored at 40 < 0 > C and 75% RH. In some embodiments, the compositions are stable for 12 months when stored at 40 < 0 > C and 75% RH and when stored at 40 < 0 > C and 75% RH.

In some embodiments, the term " stable " means that at least 85%, at least 90%, at least 95%, or at least 96% of the active agent, such as, for example, Quot; refers to, for example, a pharmaceutical composition in the dosage form. In some embodiments, the term " stable " means less than 0.8 wt / wt%, less than 0.7 wt / wt%, or less than 0.6 wt / wt%, as measured by HPLC at the end of a specified period of time, refers to a pharmaceutical composition comprising less than 0.5 wt / wt%, less than 0.5 wt / wt%, less than 0.4 wt / wt%, less than 0.3 wt / wt%, or less than 0.2 wt / wt% impurities.

In some embodiments, the present invention provides a pharmaceutical composition having an in vitro dissolution profile that dissolves rapidly. In some embodiments as described herein, dissolution is measured in 1000 mL of pH 4.5 acetate buffer using USP Apparatus Type-I at 60 占 RPM at 37 占 폚 占 .5 占 폚. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that 80%, 85%, 90%, or 92% of the drug is released after 10 minutes. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that at least 85% of the drug is released after 10 minutes. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that at least 90% of the drug is released after 10 minutes.

In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that 80%, 85%, 90%, 92%, or 94% of the drug is released after 15 minutes. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that at least 85% of the drug is released after 15 minutes. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that at least 92% of the drug is released after 15 minutes.

In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that 90%, 92%, 94%, 96%, or 98% of the drug is released after 30 minutes. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that at least 95% of the drug is released after 30 minutes. In some embodiments, the composition exhibits an in vitro dissolution profile that dissolves rapidly, such that at least 98% of the drug is released after 30 minutes.

In some embodiments, the invention provides a pharmaceutical composition of the fast-dissolving stable, e.g., dosage form, comprising:

(i) from about 1% to about 25% of dipalmitinized citrate;

(ii) from about 40% to about 90% diluent;

(iii) from about 2% to about 20% disintegration;

(iv) from about 0.5% to about 5% of a lubricant; And

(v) from about 0.1% to about 3% of a lubricant,

Wherein the total composition does not exceed 100%.

In some embodiments, the invention provides a pharmaceutical composition of the fast-dissolving stable, e.g., dosage form, comprising:

(i) from about 1% to about 25% of dipalmitinized citrate;

(ii) from about 40% to about 90% microcrystalline cellulose, lactose, or combinations thereof;

(iii) about 2% to about 20% crospovidone;

(iv) from about 0.5% to about 5% silicon dioxide; And

(v) from about 0.1% to about 3% magnesium stearate, sodium stearyl fumarate, or combinations thereof,

Wherein the total composition does not exceed 100%.

In some embodiments, the invention provides a rapidly dissolving stable pharmaceutical preparation comprising an intragranular portion and an extragranular portion, wherein the granular portion comprises:

(i) from about 1% to about 25% of dipalmitinized citrate;

(ii) from about 40% to about 90% diluent;

(iii) from about 2% to about 20% disintegration;

(iv) from about 0.5% to about 5% of a lubricant; And

(v) from about 0.1% to about 3% of a lubricant, wherein the portion in the granule does not exceed 100%; The granular outside portion comprises:

(i) from about 60% to about 95% of a diluent;

(ii) from about 5% to about 30% disintegration;

(iii) from about 1% to about 10% of a lubricant; And

(iv) about 0.1% to about 3% of a lubricant, wherein the granular portion does not exceed 100%, and wherein the composition comprises about 60% to about 95% of the granular portion and about 5% to about 40% Of the granules. In some embodiments, the composition comprises about 75% to about 90% of the granular portion and about 10% to about 25% of the granular portion, or about 80% of the granular portion and about 20% of the granular portion . The term " in granules " refers to granules comprising an active agent, and the term " outside granules " refers to granules that do not contain an active agent.

In some embodiments, the invention provides a process for preparing an oral pharmaceutical composition comprising:

(a) mixing the multiparticulated citric acid co-crystals with one or more pharmaceutically acceptable excipients to form a blend; And

(b) directly compressing the blend of step (a) into a solid dosage form.

In some embodiments, the invention provides a process for preparing an oral pharmaceutical composition comprising:

(a) mixing the multiparticulated citric acid co-crystals with one or more pharmaceutically acceptable excipients to form a blend;

(b) compressing the blend of step (a) into a slug or a compact;

(c) pulverizing the slug or compact of step (b) into granules;

(d) optionally, mixing the granules of step (c) with additional pharmaceutically acceptable excipients to form a final blend; And

(e) optionally, compressing the final blend of step (d) into a solid dosage form.

In some embodiments, the invention provides a process for preparing an oral pharmaceutical composition comprising:

(a) mixing the multiparticulated citric acid co-crystals with one or more pharmaceutically acceptable excipients to form a blend;

(b) granulating the blend of step (a) with a granulating liquid to obtain granules;

(c) drying the granules of step (b) to obtain dried granules;

(d) optionally, grinding the dried granules of step (c);

(e) adding at least one lubricant to the granulate of step (c) or to the milled material of step (d) and optionally mixing with further pharmaceutically acceptable excipients to form a final blend; And

(f) optionally, compressing the final blend of step (d) into a solid dosage form.

In some embodiments, the invention provides a method of treating diabetes, comprising administering an oral pharmaceutical composition as described herein, comprising multiparticulated citric acid crystals and one or more pharmaceutically acceptable excipients .

According to one embodiment, the method of treatment further comprises administration of an additional anti-diabetic agent.

The term " pharmaceutical composition " as used herein includes solid dosage forms such as powders, pellets, small tablets, granules, tablets, capsules and the like. In some embodiments, the compositions are in the form of powders, granules, tablets, caplets, gel caps, or capsules.

As used herein, the term " dapaglifloated citric acid crystallite " refers to a stoichiometric multi-component system comprising a dapagliflozed base and citric acid at a stoichiometric ratio of 1: 1 and connected by noncovalent interactions Quot; In some embodiments, the term " multiparticulate citric acid crystallite " is as described in WO 2015/198227, the disclosure of which is incorporated herein in its entirety. In some embodiments, the multi-phaglypholated citrate crystals are present in the composition in an amount from about 0.5% to about 25% by weight based on the total weight of the composition. Those skilled in the art will appreciate that 100% of the dipalmitinized citric acid need not necessarily be in crystalline form. Thus, as used herein, in some embodiments, the term " multiparticulated citric acid crystallite " means that at least about 80%, at least about 85%, at least about 90% , At least 98%, or at least 99% of the multipagleted citric acid is in crystalline form.

The term " anti-diabetic agent ", as used herein, includes metformin, pioglitazone, rosiglitazone, sitagliptin, linagliptin, saxagliptin, Alogliptin, pramlintide, repaglinide, nateglinide, acarbose, miglitol, glimepiride, gliburide, but are not limited to, glyburide, glipizide, and voglibose.

As used herein, the term " about " means any value within a range defined by a difference of less than +/- 10% of the value.

As used herein, the term " active moiety " refers to a dapagliflozed base. For example, 14.7 mg of dapagliflozin citrate co-crystals correspond to 10 mg of the dapagliflozole base.

The term " pharmaceutically acceptable excipients " as used herein includes diluents, binders, disintegrating agents, lubricants, lubricants, and mixtures thereof.

Various diluents may be used. In some embodiments, suitable diluents include lactose, such as lactose anhydrous and lactose monohydrate; Celluloses such as microcrystalline cellulose, co-treated microcrystalline cellulose and powdered celluloses; Starches, such as, for example, citron starch, corn starch, rice starch, potato starch and wheat starch; Sugar alcohols such as mannitol, sorbitol, xylitol and erythritol; Inorganic salts such as calcium carbonate, calcium phosphate, calcium sulfate, dibasic calcium phosphate, dibasic calcium phosphate anhydride, dibasic calcium phosphate dihydrate and tribasic calcium phosphate; And mixtures thereof. The diluent may be present in an amount of from about 20% to about 98% by weight of the composition, preferably from about 30% to about 95% by weight of the composition. In some embodiments, the diluent is from about 60% to about 90% by weight of the composition, from about 70% to about 90% by weight of the composition, or from about 80% to about 90% by weight of the composition.

According to the present invention, various binders can be used. In some embodiments, suitable binders are selected from the group consisting of povidone, copovidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose sodium, xanthan gum, acacia gum, Corn starch, corn starch, corn starch, maize starch, citron starch, methacrylate, carboxyvinyl polymer, waxes, and mixtures thereof. The starch is preferably selected from the group consisting of starches, starches, tragacanth, corn starch, corn starch, The binder may be present in an amount of from about 0% to about 30% by weight of the composition, preferably from about 0% to about 20% by weight of the composition. In some embodiments, the binder is from about 0 wt% to about 10 wt% of the composition, from about 0 wt% to about 5 wt% of the composition, or from about 0 wt% to about 1 wt% of the composition. In some embodiments, the binder is not present in the composition. That is, the composition comprises 0% binder.

According to the present invention, various decomposers can be used. In some embodiments, a suitable disintegrant is selected from the group consisting of croscarmellose sodium, hydroxypropylcellulose, crospovidone, low-substituted hydroxypropylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, starch, corn starch , Modified starch, modified starch, modified starch, sodium starch glycolate, carboxymethyl starch, polyacrylate, and mixtures thereof. The disintegrant may be present in an amount of from about 0% to about 30% by weight of the composition, preferably from about 0% to about 20% by weight of the composition. In some embodiments, the disintegrant is from about 1% to about 10% by weight of the composition, from about 1% to about 5% by weight of the composition, or from about 5% to about 7% by weight of the composition.

According to the present invention, various lubricants can be used. In some embodiments, suitable lubricants are selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, polyethylene glycol, talc, hydrogenated vegetable oils, fatty acids, waxes, ≪ / RTI > The lubricant may be present in an amount of from about 0.1% to about 10% by weight of the composition, preferably from about 0.1% to about 5% by weight of the composition. In some embodiments, the lubricant is from about 0.01 wt% to about 5 wt% of the composition, from about 0.1 wt% to about 2 wt% of the composition, or from about 1 wt% to about 2 wt% of the composition.

According to the present invention, various lubricants can be used. In some embodiments, suitable lubricants or anti-sticking agents are selected from the group consisting of talc, silicon dioxide, colloidal silicon dioxide (colloidal anhydrous silica), calcium silicate, magnesium silicate, hydrated silica, and mixtures thereof. The lubricant may be present in an amount of from about 0.1% to about 10% by weight of the composition, preferably from about 0.1% to about 5% by weight of the composition. In some embodiments, the lubricant is from about 0 wt% to about 5 wt% of the composition, from about 0.1 wt% to about 5 wt% of the composition, or from about 1 wt% to about 2 wt% of the composition.

The oral pharmaceutical composition may be prepared by a wet granulation process or by a dry process such as direct compression and dry granulation. Preferably, the pharmaceutical compositions are prepared by a dry process. The compositions may be coated or optionally not coated. In some embodiments, the oral pharmaceutical compositions are additionally film-coated using techniques well known in the art, such as spray coating or dip coating in conventional coating pans. The film coating comprises film-forming polymers and one or more coating additives. The target weight gain after coating is varied between 1 wt% and 10 wt% of the uncoated composition, between 1.5 wt% and 6 wt% of the uncoated composition, or between 2 wt% and 4 wt% of the uncoated composition .

Suitable film-forming polymers include cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and ethylcellulose; Vinyl polymers such as polyvinylpyrrolidone; Acrylic polymers; And mixtures thereof. Alternatively, commercially available coating compositions can be used in the coating, including film-forming polymers sold under a variety of trade names, such as, for example, Opadry ^® .

In some embodiments, to the subject to which the dosage form is administered, the film-coating may be applied to the immediate release, extended release, sustained release, delayed release, enteric release, Provides intestinal release. In some embodiments, the film-coating provides immediate release of the active agent.

As used herein, the term " delayed release " as used herein refers to a delayed release formulation that is substantially entirely passed over the stomach and dissolves in the small intestine and / or the colon (e.g., the colon) Substance. In some embodiments, the delayed release of the active agent (e. G., A coagulant of multipigrafloured citrate as described herein) is due to the use of an enteric coating of an oral drug (e. G., Oral dosage form) do. The term " extended release " or " sustained release " refers to a drug formulation that provides gradual release of the drug over an extended period of time, such as 6 to 12 hours or more, compared to an immediate release formulation of the same drug. In some embodiments, although not necessarily, extended release results in a blood level of the drug that is substantially constant within the therapeutic level for extended periods of time or longer. As used herein, the term " intestinal release " refers to pharmaceutical compositions for oral administration, for example, oral dosage forms, which are capable of dissolving undissolved in a high pH (low pH) environment. An enteric formulation can be obtained, for example, by incorporating a dissolution-resistant polymer in the gastric juice into the pharmaceutical composition. In some embodiments, the polymers have an optimum pH for dissolution ranging from about 5.0 to 7.0 (" pH sensitive polymers ").

The term "film-coated", "film" or "coating additives" includes one or more plasticizers, lubricants or flow control agents, lubricants, colorants and opacifiers.

Suitable plasticizers are selected from the group comprising castor oil, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, and mixtures thereof. Opacities such as titanium dioxide may also be present in the coating.

Examples of solvents used for preparing the coating solution are selected from purified water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride and mixtures thereof.

A pharmaceutical composition for oral use will be the brand name Farxiga ^® (AstraZeneca, UK) available (as propane diol monohydrate) commercially available under the spirit formulated in pageul ripple and biologically equivalent (bioequivalent).

The oral pharmaceutical composition is used for the treatment of diabetes, especially type II diabetes. The pharmaceutical composition may be administered in combination with other anti-diabetic agents. Various therapies are known to those skilled in the art. In some embodiments, the oral pharmaceutical composition is administered once a day. In some embodiments, the oral pharmaceutical composition is administered twice daily. In some embodiments, the oral pharmaceutical composition is administered every other day. One of ordinary skill in the art will also understand that in some embodiments the pharmaceutical composition may be divided (e.g., divided in half) into one or more partitions that are taken at the same time or at different times.

The invention is demonstrated hereinafter with reference to the following examples. However, those skilled in the art will understand that the specific methods and results discussed are merely illustrative of the invention and should not be construed as limiting the invention, since many modifications are possible without departing from the spirit and scope of the invention .

example

Example 1:

step:

1. Daffagliptin citrate co-crystals, microcrystalline cellulose, lactose, crospovidone and silicon dioxide were mixed in a blender.

2. Magnesium stearate was added to the blend in the blender and mixed.

3. The blend of step 2 was compressed into tablets.

4. Prepare Opadry ^® dispersions and coat the tablets of step 3 to a weight gain of 2 w / w% to 4 w / w%.

Dissolution study

Tablets of Example 1 were subjected to in vitro dissolution studies in 1000 ml of pH 4.5 acetate buffer for 30 minutes at 37 ° C ± 0.5 ° C using USP Apparatus Type-I at 60 RPM. The results are presented in Table 1 below (dissolution profile of Example 1 tablets):

Time (minutes) Cumulative Emissions (%) 10 92 15 94 30 98

Example 2:

step:

1. Daffagliptin citrate co-crystals, microcrystalline cellulose, lactose, crospovidone and silicon dioxide were mixed in a blender.

2. Magnesium stearate was added to the blend in the blender and mixed.

3. The blend of step 2 was compressed into tablets.

4. Prepare Opadry ^® dispersions and coat the tablets of step 3 to a weight gain of 2 w / w% to 4 w / w%.

Stability data:

The tablets prepared according to Example 2 were stored for 6 months at 30 DEG C, 65% RH and 40 DEG C, 75% RH and then tested by HPLC to determine the total amount of impurities. The stability data is presented in Table 2 (stability data of Example 2 tablets).

30 ° C and 65% RH 40 ° C and 75% RH first 3 months 6 months first 3 months 6 months analysis(%) 99.4 98.3 97.1 99.4 97.9 96.2 Total impurities (w / w%) 0.14 0.18 0.32 0.14 0.5 0.64

Example 3-4:

step:

1. Dopaggregate citrate co-crystals, microcrystalline cellulose, lactose, povidone, crospovidone and silicon dioxide are blended in a blender.

2. Add the magnesium stearate or sodium stearyl fumarate to the blend in the blender and mix.

3. Compress the blend of Step 2 with tablets.

4. Prepare the Opadry ^® dispersion and coat the tablets of step 3 to a weight gain of 2 w / w% to 4 w / w%.

Example 5:

step:

1. Dopaggregated citric acid co-crystals, microcrystalline cellulose, lactose anhydride, crospovidone and silicon dioxide are blended in a blender.

2. Compress the blend of step 1 and grind to obtain granules.

3. Blend the granules and extragranular excipients obtained in step 2.

4. Compress the blend of Step 3 with tablets.

5. Preparation of Opadry ^® dispersion, and coating the tablets of step 3 to the Opadry ^® dispersion up to 2 w / w% to about 4 w / w% by weight of reinforcement.

Example 6-8:

step:

1. Blend lactose anhydrous / monohydrate, microcrystalline cellulose, and dipalmitoyl citrate citrate crystals in a blender.

2. Dissolve hydroxypropylcellulose or hydroxypropylmethylcellulose or povidone in a solvent mixture or purified water to obtain a binder solution.

3. Granulate the material from step 1 into the binder solution from step 2.

4. Dry and pulverize the granules obtained in step 3.

5. Add the granular outer microcrystalline cellulose and crospovidone to the granules of step 4 and mix.

6. Add the colloidal anhydrous silica and magnesium stearate to the material of step 5 and mix.

7. Compress the blend from step 6 with tablets.

8. Preparation of Opadry ^® dispersion, and coating the tablets of step 7 with Opadry ^® dispersion up to 2 w / w% to about 4 w / w% by weight of reinforcement.

Claims (20)

An oral pharmaceutical composition comprising multiparticulated citric acid co-crystals and one or more pharmaceutically acceptable excipients,
Wherein the multiparticulated citrate co-crystal is from about 0.5% to about 25% by weight of the total weight of the composition. The method according to claim 1,
Wherein the multiparticulated citrate co-crystal in the pharmaceutical composition is from about 1 mg to about 100 mg. 3. The method according to any one of claims 1 to 2,
Wherein said pharmaceutically acceptable excipients are selected from one or more of diluents, binders, disintegrants, lubricants and mixtures thereof. 4. The method according to any one of claims 1 to 3,
Wherein said composition does not comprise a binder. 5. The method according to any one of claims 1 to 4,
Wherein the composition is in the form of a powder, pellet, compact tablet, granule, tablet or capsule. 6. The method according to any one of claims 1 to 5,
Wherein the composition further comprises a film-coating. 7. The method according to any one of claims 1 to 6,
Wherein the composition is stable for 6 months when stored at 30 占 폚, 65% RH or 40 占 폚, 75% RH. 8. The method according to any one of claims 1 to 7,
Wherein the composition exhibits an in vitro release profile in which the composition is rapidly dissolved. 9. The method of claim 8,
Wherein the composition releases more than 85% of the drug after 15 minutes when tested in 1000 mL of pH 4.5 acetate buffer at 37 ° C ± 0.5 ° C using USP device Type-I at 60 RPM . 10. The method according to any one of claims 1 to 9,
Wherein said composition is bioequivalent to commercially available Farxiga ( ^R) tablets. 11. The method according to any one of claims 1 to 10,
Wherein the composition is prepared by a wet granulation process. 11. The method according to any one of claims 1 to 10,
Wherein the composition is prepared by a dry process selected from direct compression and dry granulation. Claims 1. A process for preparing an oral pharmaceutical composition comprising multiparticulate citrate co-crystals and at least one pharmaceutically acceptable excipient, wherein the process comprises:
(a) mixing the multiparticulated citric acid co-crystals with one or more pharmaceutically acceptable excipients to form a blend; And
(b) directly compressing the blend of step (a) into a solid dosage form. Claims 1. A process for preparing an oral pharmaceutical composition comprising multiparticulate citric acid co-crystals and one or more pharmaceutically acceptable excipients, wherein the process comprises:
(a) mixing the multiparticulated citric acid co-crystals with one or more pharmaceutically acceptable excipients to form a blend;
(b) granulating the blend of step (a) with a granulating liquid to obtain granules;
(c) drying the granules of step (b) to obtain dried granules;
(d) adding at least one lubricant to the dried granules of step (c) to form a final blend. 15. The method of claim 14,
Further comprising milling the dried granules of step (c). 16. The method according to any one of claims 14 to 15,
Further comprising mixing the lubricant of step (d) with additional pharmaceutical excipients to form a final blend. 17. The method according to any one of claims 14 to 16,
Further comprising compressing the final blend of step (d) into a solid dosage form. As a method of treating type 2 diabetes mellitus,
Wherein the method comprises administering an oral pharmaceutical composition according to any one of claims 1 to 17 to a subject in need thereof. 19. The method of claim 18,
Wherein said method further comprises administration of an additional anti-diabetic agent. 20. The method of claim 19,
Wherein the additional anti-diabetic agent is selected from the group consisting of metformin, pioglitazone, rosiglitazone, cyproglitin, linagliptin, saxagliptin, allogliptin, pramlineide, repaglinide, nateglinide, acarbose, miglitol, glimepiride, ≪ / RTI &