Description :

The present invention relates to a stable pharmaceutical composition of saxagliptin or salts thereof. In particular  the invention relates to stable comprises a core and two or more layers coated on the core  wherein the composition is free of polyvinyl alcohol. Such composition of saxagliptin may exhibit relatively improved storage stability and particularly  levels of degradants in the formulation during storage can be effectively controlled. The invention also includes a process of preparing such compositions and method of treating type-II diabetes mellitus by administering the composition to a patient in need thereof.

Saxagliptin is an orally active inhibitor of the dipeptidyl peptidase-4 (DPP4) enzyme. After a meal intake  insulinotropic hormone glucagon-like peptide-1 (GLP-1) is released which in turn induces insulin release from the pancreas. Some of the GLP-1 is inactivated by the DPP4 present in plasma and intestinal capillary endothelium. Therefore  if the DPP4 is inhibited  more GLP-1 will be available to activate insulin release from the pancreas. The advantage of this mechanism of insulin release is that insulin is secreted only in response to a meal. Therefore  problems of hypoglycemia associated with other diabetes drugs are less likely with a DPP4 inhibitor.

Chemically saxagliptin is (1S 3S 5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo [3.3.1.1]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate or (1S 3S 5S)-2- [(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo [3.1.0]hexane-3-carbonitrile with the structure

Saxagliptin alone or in combination with other anti-diabetic agents are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-II diabetes mellitus in multiple clinical conditions. It is marketed in the United States in the form of tablets under the brand name Onglyza®.

It is well known in the art that saxagliptin is an unstable compound and it is prone to an intra-molecular cyclization. The resultant degradant  cyclic amidine (mainly cis-cyclic amidine) is not therapeutically active and therefore  its formation is not desirable. This cyclization reaction can occur both in solid state and solution state. The rate of intra-molecular cyclization of saxagliptin is accelerated when formulations are subject to commonly used processing activities such as wet granulation  roller compaction  or tabletting. In addition  most commonly used excipients  when mixed with saxagliptin  can accelerate the rate of cyclization. Moreover  the level of cis-cyclic amidine increases when the drug to excipient ratio increases posing more challenges for low strength dosage forms. Thus  these properties of saxagliptin posses major challenge in devising conventional and stable dosage form with ease of manufacture.

Several studies have been conducted to address the formulation and drug release systems of DPP4 inhibitor’s and attempts have also been made to improve the formulation stability.

U.S. Patent No. 6 395 767 discloses a DPP4 inhibiting compound  saxagliptin and its use in treating type-II diabetes mellitus.

PCT Publication No. WO 2011/052825 discloses a composition of DPP4 inhibitors and anti-diabetic compounds for use in the treatment of diabetes.

U.S. Patent Application Publication No. 2005/0208133 discloses a multiple drug release systems  its composition and methods of its preparation.

PCT Publication No. WO 2002/085335 discloses a composition providing control release of medicament. The composition contains several coatings  which controls the release of the medicament.

U.S. Patent No. 7 951 400 discloses a saxagliptin tablet containing several coating layers of polyvinyl alcohol.

Although various attempts have been made earlier for improving the stability of saxagliptin during the process of formulation and storage  the compositions disclosed in the prior art either suggests incorporating the drug in the core of the formulation or applying specialized polymer coatings when drug is placed in coating.

Still  there exists an enduring need for alternative  improved and stable pharmaceutical composition of saxagliptin  which exhibits excellent storage stability and that to without placing saxagliptin in the core.

The inventors of the present invention have surprisingly found that it is possible to formulate a stable pharmaceutical composition of saxagliptin  which can exhibit superior chemical and physical stability without using polyvinyl alcohol polymer in the composition.

In one general aspect  there is provided a stable pharmaceutical composition of saxagliptin or salts  hydrates thereof comprising:
(a) at least one core;
(b) at least one first coating layer coated over the core comprising one or more pharmaceutical excipients and optionally with one or more polymers;
(c) at least one second coating layer disposed over the first coating layer comprising saxagliptin or salts  hydrates thereof  one or more pharmaceutical excipients and optionally with one or more polymers; and
(d) optionally  an outer coating layer disposed over the second coating layer comprising one or more pharmaceutical excipients and optionally with one or more polymers 
wherein said core does not contain saxagliptin  or salts  hydrates thereof and the composition is free of polyvinyl alcohol.

In another general aspect  the polymer in the second coating layer and the outer coating layer is different that the polymer in the first coating layer.

In another general aspect  there is provided a tablet comprising:
(a) a core comprising one or more pharmaceutical excipients  and optionally one or more anti-diabetic agents;
(b) at least one first coating layer coated over the core comprising hydroxypropyl methylcellulose;
(c) at least one second coating layer disposed over the first coating layer comprising saxagliptin or salts  hydrated thereof  one or more pharmaceutical excipients and optionally with one or more polymers; and
(d) optionally  an outer coating layer disposed over the second coating layer comprising one or more pharmaceutical excipients and optionally with one or more polymers 
wherein said core does not contain saxagliptin  or salts  hydrates thereof and the composition is free of polyvinyl alcohol.

In another general aspect  the composition further comprises an outermost layer containing colorants and one or more polymers to differentiate compositions of various strengths. The components of the outermost layer may be similar as in the outer layer.

In another general aspect  there is provided a process for preparation of a stable pharmaceutical composition comprising saxagliptin or salts  hydrates thereof  which process comprises of:
(a) providing at least one core;
(b) coating the core with at least one first coating layer comprising one or more pharmaceutical excipients and optionally with one or more polymers;
(c) coating at least one second coating layer comprising saxagliptin or salts  hydrated thereof  one or more pharmaceutical excipients and optionally  one or more polymers over the first coating layer;
(d) optionally  coating an outer coating layer comprising one or more pharmaceutical excipients and optionally one or more polymers  over the second coating layer; and
(e) optionally  coating the outermost protective coating layer comprising one or more polymers and colorant over the outer coating layer 
wherein said core does not contain saxagliptin  or salts  hydrates thereof and the composition is free of polyvinyl alcohol.

In another general aspect  the coating layers on the core are applied by spray coating. Perforated pan coaters and fluid bed coaters can be used for the coating.

In another general aspect  in the process for preparation of stable pharmaceutical composition comprising saxagliptin or salts  hydrates thereof  the first coating layer  the second coating layer  the outer coating layer  and optionally outermost protective coating layer each are applied as a suspension of the polymer in a coating solvent.

In another general aspect  the stable pharmaceutical composition of saxagliptin or salts  hydrates thereof retains at least 90% w/w of total potency of saxagliptin after storage at 40°C and 75% relative humidity for at least 3 months.

In another general aspect  there is provided a method of treating type-II diabetes mellitus in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

The stable pharmaceutical composition of the present invention comprises saxagliptin  or salts  hydrates thereof. The composition comprises one or more cores and two or more layers coated on the core  wherein the first coat is free of polyvinyl alcohol. The core in the composition does not contain saxagliptin  or salts  hydrates thereof.

The pharmaceutical composition of the present invention exhibits excellent storage stability over the storage period.

In an embodiment  the stable pharmaceutical composition of the present invention may be characterized by lower level of degradant cis-cyclic amidine.

In another embodiment  the stable pharmaceutical composition of saxagliptin or salts  hydrates thereof retains at least 90% w/w of the total potency of saxagliptin after storage at 30°C and 60% relative humidity  at 40°C and 75% relative humidity  or at 25°C and 60% relative humidity for at least 3 months.

The term "saxagliptin" used throughout the specification refers to not only saxagliptin per se  but also various pharmaceutically acceptable salts and pharmaceutically acceptable hydrates thereof.

The term "core" used throughout the specification refers to a "core"  "tablet core"  "placebo"  "placebo core tablet"  "tablet core composition" or "core composition".

The core employed in the composition of the invention may include conventional pharmaceutical excipients to enable formation of a pharmaceutically acceptable solid core. The core may be in the form of a tablet  bead  beadlet  or pill.

In an embodiment  the core may contain one or more anti-diabetic agents  other than saxagliptin  in an amount within the range from about 0.1 to about 70% wt/wt and preferably from about 1 to about 50% w/w of the composition.

The core may be formed of one or more pharmaceutical excipients selected from  but not limited to one or more of bulking agents or fillers  binders  disintegrants  and lubricants.

In an embodiment  the core preferably contain a) at least one bulking agent or filler; b) optionally at least one binder; c) optionally at least one disintegrant; and d) preferably but optionally at least one lubricant  wherein a) the bulking agent or filler is present in an amount within the range from about 1 to about 95% w/w  preferably from about 10 to about 85% w/w; b) the binder is present in an amount within the range from about 0 to about 20% w/w  preferably from about 1 to about 10% w/w; c) the disintegrant is present in an amount within the range from about 0 to about 20% w/w  and preferably from about 0.25 to about 10% w/w; and d) the lubricant is present in an amount within the range from about 0 to about 5% w/w  preferably from about 0.2 to about 2% w/w of the composition.

In another embodiment  the bulking agents are microcrystalline cellulose and lactose monohydrate; the disintegrant is croscarmellose sodium; and the lubricant is magnesium stearate.

The cores present in the composition of the invention can be prepared by a variety of processes and order of addition of excipients. The utility of these formulations is not limited to a specific dosage form or manufacturing process. The cores may be manufactured by wet granulation  dry granulation  direct blending or any other pharmaceutically acceptable process.

In an embodiment  the process of preparing the cores includes the steps of blending the one or more excipients such as bulking agent  optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate tablet formation.

The bulking agents or fillers may be present in the core in an amount within the range from about 1 to about 95% w/w and preferably from about 10 to about 85% w/w of the composition. Examples of bulking agents or fillers suitable for use herein include  but are not limited to  cellulose derivatives such as microcrystalline cellulose or wood cellulose  lactose  sucrose  starch  pregelatinized starch  dextrose  mannitol  fructose  xylitol  sorbitol  corn starch  modified corn starch  inorganic salts such as calcium carbonate  calcium phosphate  dicalcium phosphate  calcium sulfate  dextrin/dextrates  maltodextrin  compressible sugars  and other known bulking agents or fillers  and/or mixtures thereof  preferably microcrystalline cellulose.

The binder may be present in the core in an amount within the range from about 0 to about 20% w/w  preferably from about 1 to about 10% w/w of the composition. Examples of binders suitable for use herein include  but are not limited to  hydroxypropyl cellulose  corn starch  pregelatinized starch  modified corn starch  polyvinyl pyrrolidone (PVP) (molecular weight ranging from about 5 000 to about 1 000 000  preferably about 40 000)  hydroxypropyl methylcellulose (HPMC)  lactose  gum acacia  ethyl cellulose  cellulose acetate  as well as a wax binder such as carnauba wax  paraffin  spermaceti  polyethylenes or microcrystalline wax  as well as other conventional binding agent and/or mixtures thereof  preferably hydroxypropyl cellulose.

The disintegrant may be present in the core in an amount within the range from about 0 to about 20% w/w  preferably from about 0.25 to about 10% w/w of the composition. Examples of disintegrants suitable for use herein include  but are not limited to  croscarmellose sodium  crospovidone  starch  potato starch  pregelatinized starch  corn starch  sodium starch glycolate  microcrystalline cellulose  low substituted hydroxypropyl cellulose or other known disintegrant  preferably croscarmellose sodium.

The lubricant may be present in the core in an amount within the range from about 0.1 to about 5% w/w  preferably from about 0.2 to about 2% w/w of the composition. Examples of tableting lubricants suitable for use herein include  but are not limited to  magnesium stearate  zinc stearate  calcium stearate  talc  carnauba wax  stearic acid  palmitic acid  sodium stearyl fumarate or hydrogenated vegetable oils and fats  or mixtures thereof  preferably magnesium stearate.

The first coating layer of the composition comprises one or more pharmaceutical excipients and optionally one or more polymers.

The amount of polymer in the first coating layer is more than 50% by weight of polymer  preferably more than 80% by weight of polymer  and most preferably more than 90% by weight of polymer relative to the total weight of the first coating layer.

The coating formulation for first coating contains at least one polymer and a coating solvent  which preferably is water  which is used for processing and removed by drying. Suitable polymer for first coating layer may be selected from  but not limited water-soluble polymer  water-insoluble polymer  or mixtures thereof. Particularly  water-soluble polymers are preferred.

Examples of polymers suitable for first coating layer include  but not limited to hydroxypropyl methylcellulose  ethyl cellulose  methacrylic polymers or hydroxypropyl cellulose  preferably hydroxypropyl methylcellulose. The coating layer may also optionally include a plasticizer such as triacetin  diethyl phthalate  tributyl sebacate or polyethylene glycol (PEG)  preferably PEG; and an anti-adherent or glidant such as talc  fumed silica or magnesium stearate  opacifying agent such as titanium dioxide. The coating layer may also include iron oxide based colorants.

Examples of suitable coating solvents includes  but not limited to water  ethanol  methanol  and isopropyl alcohol  with water being preferred.

The first coating layer which is free of polyvinyl alcohol will preferably be formed by coating polymer layer in an amount within the range from about 10 to about 99%  preferably from about 20 to about 99% w/w of the first coating layer  optionally plasticizer in an amount within the range from about 1 to about 30%  preferably from about 5 to about 20% w/w of the first coating layer  and anti-adherent or glidant in an amount within the range for about 15 to about 30%  preferably from about 10 to about 15% w/w of the first coating layer.

The first coating layer may be present in an amount within the range from about 1 to about 5%  preferably from about 1 to about 3% w/w of the composition.

The second coating layer of the composition of the invention comprises saxagliptin  or salts  hydrates thereof  one or more pharmaceutical excipients and optionally  one or more polymers. Suitable coating solvent is employed to facilitate the coating  which preferably is water  which is used for processing and removed by drying.

The amount of saxagliptin  or salts  hydrates thereof in the second coating layer is in the range from about 0.25 to about 70%  preferably from about 20 to about 50% w/w  based on the weight of the second coating layer.

The amount of polymer in the second coating layer may range from about 30 to about 99.5%  preferably from about 40 to about 60% w/w of the second coating layer.

The second coating layer (containing saxagliptin) may be present in an amount within the range from about 0.25 to about 70%  preferably from about 1 to about 50% w/w of the composition.

The outer coating layer of the composition of the invention comprises one or more pharmaceutical excipients and optionally  one or more.

In an embodiment  the composition of the invention includes an outer layer where the coating suspension is prepared as in the case of the second coating suspension but without saxagliptin. The coating suspension is then can be coated onto the previously coated composition as described for the first coating and second coating to form a protective coating layer thereon.

The outer protective coating layer will preferably be similar in composition to the second coating layer except without containing saxagliptin.

The composition of the present invention further may comprise an outermost protective layer comprising one or more polymers and one or more pharmaceutical excipients.

The outermost coating layer where present will preferably be similar in composition to the outer protective coating layer and will include colorant as desired  such as within the range from about 0.5 to about 5.0% w/w  based on the total weight of the outermost coating layer.

The outer and outermost protective coating layer if present  may each be present in an amount within the range from about 1 to about 10%  preferably from about 1 to about 5% w/w of the composition.

Pharmaceutical excipients suitable for employing in the coating layers of the composition may include  nut not limited to  bulking agents or diluents  binders  plasticizers  lubricants  colorants  pH adjusting agents  or mixtures thereof.

The invention further provides a process for preparation of stable pharmaceutical composition of saxagliptin or salts  hydrates thereof  the process comprises of:
(a) providing at least one core;
(b) coating the core with at least one first coating layer comprising one or more pharmaceutical excipients and optionally  one or more polymers;
(c) drying the coated core to form first coating thereon;
(d) coating at least one second coating layer comprising saxagliptin or salts  hydrates thereof  one or more pharmaceutical excipients and optionally  one or more polymers over the first coating layer;
(d) drying the coated core to form second coating thereon;
(e) optionally  coating an outer coating layer comprising one or more pharmaceutical excipients and optionally  one or more polymers over the second coating layer;
(e) optionally  drying the coated core to form outer coating thereon;
(f) optionally  coating the outermost protective coating layer comprising one or more coating polymer and colorant over the outer coating layer; and
(g) optionally  drying the coated core to form outermost coating thereon.

In a further embodiment  in preparing the coated composition of the invention  coating suspensions which include coating polymer in water are prepared. Other coating solvents which may be employed include ethanol  methanol  and isopropyl alcohol  with water being preferred. Composition  which is placebo (contain no medicament) and formed cores are coated with the first coating suspension and are dried. The second coating layer suspension containing medicament and coating polymer is applied over the so-coated cores  which are then dried.

The cores present in the composition of this invention can be prepared by a variety of processes and order of addition of excipients. The utility of these formulations is not limited to a specific dosage form or manufacturing process. The cores may be manufactured by wet granulation  dry granulation  direct blending or any other pharmaceutically acceptable process.

In accordance with the present invention  a preferred method is provided for preparing the cores employed in the composition of the invention which includes the steps of blending the one or more excipients such as bulking agent  optionally binder and optionally disintegrant. A lubricant will be preferably added to the blend to facilitate tablet formation.

It has been surprisingly found that the coated composition of the present invention exhibits superior chemical and physical stability as compared to composition containing polyvinyl alcohol in all the coating coatings or traditional tablets manufactured using conventional dry granulation or wet granulation.

The composition of the present invention may be formulated in suitable a dosage form including  but not limited to  a tablet  caplet  mini-tablet  pellets  granules  capsule filled with mini-tablets or pellets or combinations thereof.

The present invention further provides a method of treating type-II diabetes mellitus in a patient which method comprising administering the pharmaceutical composition as substantially described herein to the patient.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

In accordance with the Present Invention coated tablet formulations are set out below.

Example 1: Saxagliptin Tablet
Table 1
Sr. No. Ingredients Qty/Tab
Core Tablets
1 Lactose Monohydrate 98.00
2 Microcrystalline Cellulose 90.0
3 Croscarmellose sodium 10.0
4 Magnesium Stearate 2.00
Total 200.00
Drug Coating
5 Saxagliptin HCl anhydrous (Amorphus) 5.60
6 Hypromellose or HPC or PVP or vinylpyrrolidone-vinyl acetate and Glyceryl Caprylocaprate 5.60
7 PEG 6000 1.00
8 Talc 1.00
9 Titanium dioxide 2.00
10 Dichloromethane qs
11 Methanol qs
Film Coating
12 Opadry 5.0
Total 220.2

Process: Core tablet was prepared by mixing lactose  microcrystalline cellulose and croscarmellose sodium  followed by lubrication by mixing with magnesium stearate and compression.

A coating suspension was prepared by blending saxagliptin hydrochloride anhydrous with hypromellose/ hydroxy propyl cellulose/ PVP/ vinylpyrrolidone-vinyl acetate and Glyceryl Caprylocaprate  PEG  Talc and Titanium dioxide.

The coating suspension was then coated over the core tablet and desired weight gain was achieved.

A film coat of opadry was then applied over the drug-coated tablet followed by drying of the film coat.

We Claim

1. A stable pharmaceutical composition of saxagliptin or salts  hydrates thereof comprising:
(a) at least one core;
(b) at least one first coating layer coated over the core comprising one or more pharmaceutical excipients  and optionally one or more polymers;
(c) at least one second coating layer disposed over the first coating layer comprising saxagliptin or salts  hydrated thereof  one or more pharmaceutical excipients  and optionally  one or more polymers; and
(d) optionally  an outer coating layer disposed over the second coating layer comprising one or more pharmaceutical excipients  and optionally  one or more polymers 
wherein said core does not contain saxagliptin  or salts  hydrates thereof and the composition is free of polyvinyl alcohol.

2. The stable pharmaceutical composition of claim 1  wherein the first coating layer comprises one or more water-soluble polymer.

3. The stable pharmaceutical composition of claim 2  wherein the water-soluble polymer comprises hydroxypropyl methylcellulose.

4. The stable pharmaceutical composition of claim 1  wherein the first coating layer comprises from about 20% to about 99% w/w of polymer.

5. The stable pharmaceutical composition of claim 1  wherein the polymer in the first coating layer is different than the polymer in the second and outer coating layers.

6. The stable pharmaceutical composition of claim 1  wherein the composition retains at least 90% w/w of the total potency of saxagliptin after storage at 30°C and 60% relative humidity for at least 3 months.

7. A process for preparation of stable pharmaceutical composition of claim 1  which process comprises of:
(a) providing at least one core;
(b) coating the core with at least one first coating layer comprising one or more pharmaceutical excipients  and optionally  one or more polymers;
(c) coating at least one second coating layer comprising saxagliptin or salts  hydrated thereof  one or more pharmaceutical excipients  and optionally  one or more polymers over the first coating layer;
(d) optionally  coating an outer coating layer comprising one or more pharmaceutical excipients  and optionally  one or more polymers over the second coating layer; and
(e) optionally  coating the outermost protective coating layer comprising one or more pharmaceutical excipients  colorant  and optionally one or more polymers over the outer coating layer.

8. A stable pharmaceutical composition of saxagliptin or salts  hydrates thereof comprising:
(a) at least one core;
(b) at least one first coating layer coated over the core comprising one or more polymers;
(c) at least one second coating layer disposed over the first coating layer comprising saxagliptin or salts  hydrated thereof and one or more polymers; and
(d) optionally  an outer coating layer disposed over the second coating layer comprising one or more polymers 
wherein said core does not contain saxagliptin  or salts  hydrates thereof and the composition is free of polyvinyl alcohol.

Dated this 20th day of December 2012 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory