CA3085455C

CA3085455C - A solid oral dosage form comprising linagliptin

Info

Publication number: CA3085455C
Application number: CA3085455A
Authority: CA
Inventors: Ali Turkyilmaz; Nur Pehlivan Akalin; Merve Ergun Donmez
Original assignee: Sanovel Ilac Sanayi ve Ticaret AS
Priority date: 2017-12-15
Filing date: 2018-12-14
Publication date: 2022-08-16
Anticipated expiration: 2038-12-14
Also published as: EP3723761A4; WO2019203755A3; CA3085455A1; EP3723761A2; TR201720515A2; WO2019203755A2

Abstract

The present invention relates to a solid oral dosage form comprising linagliptin and at least one binder.

Description

A SOLID ORAL DOSAGE FORM COMPRISING LINAGLIPTIN

Field of the Invention The present invention relates to a solid oral dosage form comprising linagliptin and at least one binder.

Background of the Invention Linagliptin is used for type 2 or non-insulin dependent diabetes. It is a selective, orally administered, xanthine based dipeptidyl peptidase-4 (DPP-4) inhibitor used as an adjunct to diet and exercise to improve glycemic control. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin. There are two types of incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. Linagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.

The chemical name of linagliptin is 8-[(3R)-3-aminopiperidin-1-y1]-7-but-2-yn- 1-y1)-3-methyl-1- [(4-methylquinazolin-2-Amethyl]-3,7-dihydro-1H-purine-2,6-dione and its chemical structure is shown in the Formula I. 11110) N

N\ 0 N N

Formula I

W02014/026939 patent application discloses a pharmaceutical composition comprising linagliptin or salts thereof with mannitol, copovidone, and magnesium stearate, a process for the preparation of the pharmaceutical composition.

There still remains a need in the art to provide an improved pharmaceutical composition of linagliptin. At this invention provides having high stability of linagliptin, dissolution rate, and therefore a high bioavailability and a long-term stability.

Detailed Description of the Invention The main object of the present invention is to provide high stability of linagliptin and a long shelf life by the help of selection of excipients in a certain ratio.

Another aim of the present invention is to provide a pharmaceutical dosage form comprising linagliptin which has a long shelf life, a short disintegration time, desired dissolution properties and enables a high bioavailability of linaglitpin in a patient.

The term "linagliptin" as used throughout the specification refers to not only linagliptin, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The linagliptin is present as amorphous linagliptin, crystalline linagliptin having polymorphic form A, crystalline linagliptin having polymorphic form B and/or crystalline linagliptin having polymorphic form C or mixtures thereof.

In one embodiment of the invention, the linagliptin is present as a mixture of crystalline linagliptin having polymorphic form A and crystalline linagliptin having polymorphic form B.

In one embodiment of the invention, the pharmaceutical solid oral dosage form comprises linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to binder is between 0.1 and 6.0. This ratio is important in order to providing high stability of linagliptin and improved flow properties.

In one embodiment of the invention, the weight ratio of linagliptin to binder is between 0.3 and 3.0 or between 0.5 and 2.0.

In one embodiment of the invention, the amount of linagliptin in the composition is between 1.0% and 10.0% by weight, preferably it is between 2.0% and 7.0%, more preferably it is between 2.5% and 6.0%.

As used here in, 'particle size' means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e.

Malvern Mastersizer 2000 analysis). The term d (0.9) means the size at which %90 by volume of the particles are finer.

In one embodiment of the invention, linagliptin has ad (0.9) particle size less than 100 pm, preferably linagliptin has a d (0.9) particle size less than 50 pm. This property provides improved flow properties.

Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, mannitol, gelatin, pullulan, sodium alginate or mixtures thereof.

The present invention comprises one or more binders in an amount of from about 1% to about 20% by weight of the composition.

In general, DPP-4 inhibitors are not very stable compounds. Especially, in solid dosage forms, amine group containing DPP-4 inhibitors like linagliptin may react with many excipients or impurities of excipients. In this invention, it has been surprisingly found that using binder ensures high stability of linagliptin in a solid oral dosage composition. Especially povidone is used as binder in the present invention. Povidone has also disintegration property and it is used to enhance dissolution of poorly soluble drugs from solid-dosage forms.

In one embodiment of the invention, binder is povidone and the amount of povidone in the composition is 1.0% and 5.0% by weight.

In another embodiment, the pharmaceutical acceptable excipients used in the present invention are selected from the group consisting of fillers, disintegrants, lubricants, and film coating agents.

Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

According to one embodiment, microcrystalline cellulose is a filler which has the best flowability properties among the other fillers. In this invention, it further improves the disintegration of compositon as well as being a filler. In addition, it further enhances the compressibility by increasing the hardness of the tablet.

In this embodiment, the amount of microcrystalline cellulose is in the range of 70.0 to 90 `)/0, preferably 76.0 to 88.0 `)/0, more preferably it is 80.0 to 85.0 `)/0 by weight of total composition.

Suitable disintegrants are selected from the group comprising sodium starch glycolate, cross- linked polyvinil pyrrolidone (crospovidone), povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, sodium dodecyl sulphate, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.

Asufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient should be used to form solid oral dosage forms provided herein. However, disintegrants can be mixed with other excipient to increase effective disintegration of the tablet into smaller fragments.

In one embodiment of the invention, disintegrant is sodium starch glycolate, is also known as superdisinteg rant, and the amount of sodium starch glycolate is in the range of 3.0% to 8.0% and thus desired level of dissolution rate is provided.

Furthermore, the combination of povidone and sodium starch glycolate provides desired short disintegration time and desired dissolution properties in composition.

According to an embodiment of the present invention, the weight ratio of sodium starch glycolate to povidone is between 0.2 and 10.0 or 0.6 and 8.0.

According to another embodiment, the lubricant is selected from the group comprising sodium stearyl fumarate, magnesium stearate, polyethylene glycol (PEG), sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, paraffin or mixtures thereof, preferably sodium stearyl fumarate.

Coating may also preferably be used for moisture protection. Suitable coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, glycerine, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), 5 ethylcellulose dispersions (Sureleasee), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry , pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.

Suitable coloring agents are selected from the group comprising ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), ponceau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.

Preferably, the pharmaceutical composition of the present invention comprises linagliptin or a pharmaceutically acceptable salt thereof, povidone, sodium stearyl fumarate, sodium starch glycolate, microcrystalline cellulose.

Solid oral dosage is used for having effective stability and bioavailability.

Another embodiment of the present invention is a pharmaceutical composition in the form of a solid oral dosage form.

In this present invention, the solid oral dosage form is tablet or capsule or pastilles or strip. .. In this present invention, the solid oral dosage form is tablet. Tablet may be consisted of separated compartments or layer.

An embodiment of this present invention, the pharmaceutical combination is formulated as tablets comprising film-coated tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, pellet in tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, core-in-tablet, modified release tablets, tablet-in-tablet, orally disintegrating tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges.

Preferably, the pharmaceutical combination is formulated as film coated tablet.

In this present invention, the pharmaceutical combination can be prepared in tablet form.

Tablet comprises at least one type of particle, for example; mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.

An embodiment of this present invention, each type of particle comprises at least one active agent.

In this present invention, pharmaceutical combination may comprise a film coating if necessary.

In this present invention, pharmaceutical combination can be prepared in capsule form.

Capsule comprises of at least one type of particle, for example; mini- capsules, mini-tablets, pellets, agglomerates, granules, powders, liposomes, sphericles or mixtures thereof.

An embodiment of this present invention, the dosage unit form of composition is mini- capsules in capsule wherein the mini-capsules comprise at least one active agent.

An embodiment of this present invention, the dosage unit form of composition is mini-tablets in capsule wherein a mini-tablets comprise at least one active agent.

An embodiment of this present invention, the dosage unit form of composition is pellets in capsule wherein pellets comprise at least one active agent.

In one embodiment of the present invention, the composition comprises; a) 2.0 - 10.0% by weight of linagliptin b) 80.0 - 85.0% by weight of filler c) 1.5 - 4.0% by weight of binder d) 3.5 - 6.0% by weight of disintegrant e) 0.1 - 3.0% by weight of lubricant f) 1.0 - 5.0% by weight of coating agents In one embodiment of the present invention, the composition comprises; a) 1.0 - 10.0% by weight of linagliptin b) 70.0 - 90.0% by weight of microcrystalline cellulose c) 1.0 - 5.0% by weight of povidone d) 3.0 - 8.0% by weight of sodium starch glycolate e) 0.1 - 5.0% by weight of sodium stearyl fumarate f) 0.5 - 8.0% by weight of coating agents The pharmaceutical composition of the present invention can be prepared, using standard .. techniques and manufacturing processes well known in the art, such as direct compression, wet and dry granulation.

According to one embodiment of the present invention, it has been found that when the formulation is prepared with wet granulation, the formulation has desired stability and desired dissolution rate.

Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol or mixtures thereof, preferably the granulation solution is pure water.

An embodiment of the present invention, the process for preparation of the pharmaceutical composition comprises the following steps: a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) Drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents. 35 Example 1: Film coated tablet comprising linagliptin ( /0) amount (w/w) Linagliptin 2.0% - 10.0%

Filler 80.0% - 85.0%

Binder 1.5% - 4.0%

Disinteg rant 3.5% - 6.0%

Lubricant 0.1% - 3.0%

Coating agents 1.0% - 5.0%

Total 100 Example 2: Solid oral dosage form comprising linagliptin ( /0) amount (w/w) Linagliptin 1.0% - 10.0%

Microcrystalline cellulose 70.0% - 90.0%

Povidone 1.0% - 5.0%

Sodium starch glycolate 3.0% - 8.0%

Sodium stearyl fumarate 0.1% - 5.0%

Coating agents 0.5% - 8.0%

Total 100 Process for example 1 or 2:

The process for preparation of the pharmaceutical composition comprises the following steps: a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.

Claims

9 CLAIMS:

1. A pharmaceutical solid oral dosage form comprising linagliptin as the active agent and at least one binder in which the weight ratio of linagliptin to binder is between 0.1 and 6.0; wherein the binder is povidone.

2. The pharmaceutical solid oral dosage form according to claim 1, wherein the weight ratio of linagliptin to binder is between 0.3 and 3.0.

3. The pharmaceutical solid oral dosage form according to claim 2, wherein the weight ratio of linagliptin to binder is between 0.5 and 2.0.

4. The pharmaceutical solid oral dosage form according to claim 3, wherein the amount of linagliptin in the composition is between 1.0% and 10.0% by weight.

5. The pharmaceutical solid oral dosage form according to claim 4, wherein the amount of linagliptin in the composition is between 2.0% and 7.0% by weight.

6. The pharmaceutical solid oral dosage form according to claim 4, wherein linagliptin has a d (0.9) particle size less than 100 pm.

7. The pharmaceutical solid oral dosage form according to claim 5, wherein linagliptin has a d (0.9) particle size less than 50 pm.

8. The pharmaceutical solid oral dosage form according to any one of claims 1-7, wherein the amount of povidone in the composition is 1.0% and 5.0% by weight.

9. The pharmaceutical solid oral dosage form according to any one of claims 1-8, further comprising pharmaceutical acceptable excipients which are selected from the group consisting of fillers, disintegrants, lubricants and film coating agents.

10.The pharmaceutical solid oral dosage form according to claim 9, wherein disintegrant is selected from the group consisting of sodium starch 10 glycolate, cross-linked polyvinyl pyrrolidone (crospovidone), povidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, sodium dodesyl sulphate, sodium glycine carbonate and sodium lauryl sulphate .

11.The pharmaceutical solid oral dosage form according to claim 10, wherein disintegrant is sodium starch glycolate.

12.The pharmaceutical solid oral dosage form according to claim 11, wherein the amount of sodium starch glycolate is in the range of 3.0% to 8.0%.

13.The pharmaceutical solid oral dosage form according to claim 8 or 12, wherein the weight ratio of sodium starch glycolate to povidone is between 0.2 and 10.0.

14.The pharmaceutical solid oral dosage form according to any one of claims 1-13, wherein the solid oral dosage form is tablet or capsule or pastilles or strip.

15.The pharmaceutical solid oral dosage form according to claim 14, wherein the solid oral dosage form is tablet.

16.The pharmaceutical solid oral dosage form according to claim 15, the composition comprising; a) 2.0 - 10.0% by weight of linagliptin b) 80.0 - 85.0% by weight of filler c) 1.5 - 4.0% by weight of binder d) 3.5 - 6.0% by weight of disintegrant e) 0.1 - 3.0% by weight of lubricant f) 1.0 - 5.0% by weight of coating agents. 11

17.The pharmaceutical solid oral dosage form according to claim 15, the composition comprising; a) 1.0 - 10.0% by weight of linagliptin b) 70.0 - 90.0% by weight of microcrystalline cellulose c) 1.0 - 5.0% by weight of povidone d) 3.0 - 8.0% by weight of sodium starch glycolate e) 0.1 - 5.0% by weight of sodium stearyl fumarate f) 0.5 - 8.0% by weight of coating agents.

18.Process for preparing the pharmaceutical solid oral dosage form as defined in claim 17, comprising the following steps; a) Mixing linagliptin, microcrystalline cellulose and sodium starch glycolate b) Granulating povidone with pure water on a separate tank c) Mixing step (a) mixture and step (b) mixture d) Drying the mixture, then sieving the mixture e) Adding sodium stearyl fumarate and then mixing f) Then, pressing to form tablet g) Coating tablets with coating agents.