DESC:The present invention relates to a pharmaceutical composition comprising fixed dose combinations of Linagliptin or its pharmaceutically acceptable salt thereof and Metformin or its pharmaceutically acceptable salt thereof with stabilizing agent and one or more pharmaceutically acceptable excipients.
The present invention is relates to a pharmaceutical oral dosage form composition comprising an intra-granular portion contain Metformin and Linagliptin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the binder solution is prepared by adding the pharmaceutical acceptable excipients with Linagliptin or its pharmaceutically acceptable salts, and mix with stabilizing agent sufficient to suppress degradation of Linagliptin, and add the excipients in the extra-granular portion, lubricate and compress and cote the tablet.
The present invention relates to preparation of fixed dose solid oral pharmaceutical composition comprising Linagliptin and Metformin or its pharmaceutically acceptable salt thereof, wherein the Linagliptin is incorporated in the binder solution and added to the other pharmaceutical acceptable excipients.
The term "pharmaceutical acceptable excipient" as used herein refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients. Suitable excipients include diluents, binders, disintegrant, surfactants, lubricants, glidants, Stabilizing agent and coloring agents and the like or mixture thereof and optionally a pharmaceutical acceptable excipient.
The term “composition” or “pharmaceutical composition” or “solid dosage forms” such as granules, pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The term “pharmaceutically acceptable salts” as used herein refers to when the exemplary compounds contain an acidic group as well as a basic group, the compounds can form internal salts, which can also be used in the compositions and methods described herein. When an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth, incorporated herein by reference. Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.
The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The term “Linagliptin” as used herein means Linagliptin or its pharmaceutically acceptable salts. Linagliptin may be in amorphous form, crystalline form, a mixture thereof or co-crystals with suitable co-formers. Preferably, Linagliptin base is in crystalline anhydrous form A.
The term “Metformin” as used herein means Metformin or its pharmaceutically acceptable salts. Metformin may be in amorphous form, crystalline form, a mixture thereof or co-crystals with suitable co-formers. Preferably, Metformin HCL.
Throughout this specification, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.
The term “impurity” or “impurities,” as used herein, means those impurities specifically described herein, those derived from the process including reagents or solvents used in the process, intermediates used in the process or degradants including degradants of the compound synthesized in the process.
The term "oral dosage forms" includes all conventional oral solid dosage forms like a tablet, capsule, syrups, suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising active ingredient and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.
The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
The terms “treat” and “treating” as used herein refers are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising active ingredient or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.
According to the embodiments of the present invention diluent/ Glidant are selected from the group comprising of, micro crystalline cellulose, starch, colloidal silicon dioxide, pregelatinized starch, calcium carbonate, dibasic, tribasic calcium phosphate, calcium phosphate, lactose, dextrose, calcium phosphate, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltose, simethicone, sodium chloride, talc, xylitol, sorbitol, mannitol, maltodextrin and mixtures thereof.
The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
According to the embodiments of the present invention glidant are selected from the group comprising of, ascorbyl palmitate, calcium palmitate, magnesium stearate, colloidal silicon dioxide, starch and talc
According to the embodiments of the present invention suitable binders used according to the present invention are selected from the group comprising of co-povidone, hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and the like or combination thereof.
According to the embodiments of the present invention disintegrant are selected from the group comprising of corn starch, croscarmellose sodium, carmellose, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low-substituted hydroxypropylcellulose, crospovidone and mixtures thereof.
According to the embodiments of the present invention suitable surfactants are selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and mixtures thereof.
According to the embodiments of the present invention lubricant selected for the group anti-tacking agent, sodium lauryl sulphate, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearylfumarate, sodium benzoate, mineral oil, glycerine fumarate and mixtures thereof.
According to the embodiments of the present invention stabilizing agent selected for the group of alkaline salts of metals which may be organic or inorganic source also includes basic amino acids and their derivatives more preferably L-arginine, L-lysine or L-histigine, meglumine. A preferred stabilizing agent within the meaning of this invention is meglumine.
According to the embodiments of the present invention is relates to a solid fixed dose oral pharmaceutical composition comprising the process for the preparation of oral pharmaceutical compositions, wherein the method of manufacturing comprises blended Metformin HCl dry mix, prepare binder solution preparation by disperse Linagliptin in Purified water under stirring to form a uniform dispersion, add co-povidone and meglumine, slowly under continuous stirring and stir continuously to form a uniform dispersion, perform the granulation to above mixtures and wet mill the granules and dry the above content in rapid dryer, sizing and milling the above content, sift corn starch, colloidal silicon dioxide, magnesium stearate, lubricate the above mix using magnesium stearate, compress the above blend by using suitable tooling and Coat the tablets with film coating material.
In an embodiment, the present invention is directed to a pharmaceutical composition an oral solid tablet dosage form comprising a Linagliptin; a partner drug particularly metformin; and meglumine for stabilizing the composition and/or the Linagliptin, particularly against chemical degradation; as well as one or more pharmaceutical excipients.
In an embodiment the dosage typically required of the Linagliptin mentioned herein when administered orally is 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day. Thus, the dosage required of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine when administered orally is 0.5 mg to 10 mg per patient per day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.
In an embodiment the dosage strengths of the metformin hydrochloride for use in the present invention may be from 100 mg to 2000 mg or from 250 mg to 2000 mg, preferably from 250 mg to 1000 mg. Particular dosage strengths may be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.
In one of the embodiment of the present invention relates to a pharmaceutical oral dosage form comprising of fixed dose solid oral pharmaceutical composition comprising Linagliptin or its pharmaceutically acceptable salt thereof and Metformin or its pharmaceutically acceptable salt thereof.
In one of the embodiment of the present invention relates to a pharmaceutical oral dosage form comprising Metformin or its pharmaceutically acceptable salts and Linagliptin or its pharmaceutically acceptable salts along with a stabilizing agent and one or more pharmaceutically acceptable excipients.
In one of the embodiment of the present invention relates to a pharmaceutical oral dosage form comprising Metformin or its pharmaceutically acceptable salts, wherein the binder solution is prepared by adding the pharmaceutical acceptable excipients with Linagliptin or its pharmaceutically acceptable salts, and mix with stabilizing agent in an amount sufficient to suppress degradation of Linagliptin.
In one of the embodiment of the present invention relates to a fixed dose solid oral composition comprising Metformin or its pharmaceutically acceptable salt thereof is present in an amount of about 1% -90% w/w, Linagliptin or its pharmaceutical acceptable salt in an amount of about 5-15% based on the total weight of the composition.
In one of the embodiment of the present invention relates to a fixed dose solid oral composition comprising the extra granular portion comprising pharmaceutical acceptable excipients in an amount of 2-4% based on the total weight of the composition.
In one of the embodiment of the present invention is relates to a fixed dose solid comprising of a nucleophilic and/or basic agent, which is sufficient for stabilizing oral composition of Linagliptin, wherein the nucleophilic and/or basic agent are selected from the group L-arginine, Meglumine, L-lysine or L-histigine along with one or more pharmaceutically acceptable excipients.
In one of the embodiment of the present invention relates to a solid fixed dose oral pharmaceutical composition comprising the pharmaceutically acceptable excipients are selected from diluents, binders, disintegrant, surfactants, lubricants, glidants, stabilizing agent and coloring agents and the like or mixture thereof and optionally one or more pharmaceutical acceptable excipient.
In one of the embodiment of the present invention relates to a solid fixed dose oral pharmaceutical composition comprising a Linagliptin or its pharmaceutical acceptable salt and Metformin or its pharmaceutical acceptable salt, and a nucleophilic and/or basic agent.
In one of the embodiment of the present invention relates to a solid fixed dose oral pharmaceutical composition comprising the Linagliptin and Metformin or its pharmaceutically acceptable salts is prepared by granulation technique; preferably wet granulation.
In one of the embodiment of the present invention is relates to a solid fixed dose oral pharmaceutical composition comprising the oral dosage form is more preferably immediate release tablet dosage form.
In one of the embodiment of the present invention is relates to a solid fixed dose oral pharmaceutical composition comprising the excipients are selected from Co-povidone, Corn starch, Colloidal silicon dioxide and Magnesium stearate.
In one of the embodiment of the present invention is relates to a process for preparation of solid fixed dose oral pharmaceutical composition comprising of Linagliptin or its pharmaceutically acceptable salts, where in the binder solution is prepared by mixing the Linagliptin with other pharmaceutical acceptable excipients.
In one of the embodiment of the present invention is relates to preparation of oral pharmaceutical compositions, wherein the method of manufacturing comprises sift milled Metformin HCl through mesh and dry mix, prepare binder solution preparation by disperse Linagliptin in purified water under stirring to form a uniform dispersion, add co-povidone and Meglumine, slowly under continuous stirring and stir continuously to form a uniform dispersion, perform the granulation to above mixtures and wet mill the granules through 8mm screen, dry the above content in rapid dryer, sizing and milling the above content, sift corn starch, colloidal silicon dioxide, magnesium stearate, lubricate the above mix using magnesium stearate, compress the above blend by using suitable tooling and coat the tablets with film coating material.
The present invention relates to a pharmaceutical oral dosage form comprising Metformin or its pharmaceutically acceptable salts and Linagliptin or its pharmaceutically acceptable salts contain dissolution data shows 95% of drug release with in 30min for Linagliptin contain medium 0.1 N HCL, volume 900ml and RPM 50.
The present invention relates to a pharmaceutical oral dosage form comprising Metformin or its pharmaceutically acceptable salts and Linagliptin or its pharmaceutically acceptable salts contain dissolution data shows 95% of drug release with in 45min for Metformin contain medium 0.1 N HCl, volume 900ml and RPM 50.
Comparative multimedia dissolution profiles of reference product Vs test product:
Table 1: Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCL for Linagliptin
Product name Reference product
Ondero Met (Linagliptin metformin HCl tablets) 2.5mg/1000mg Test product
Linagliptin metformin HCl tablets) 2.5mg/1000mg
Batch number 1080604 LIMT15-0169-005
Condition Time % Drug Release
Medium: 0.1N HCL 05 Min 39 46
10 Min 71 82
15 Min 94 93
20 Min 98 93
30 Min 98 93

Figure 1. Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCl for Linagliptin

Table 2: Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCl for Metformin
Product name Reference product
Ondero Met (Linagliptin metformin HCl tablets) 2.5mg/1000mg Test product
Linagliptin metformin HCl tablets) 2.5mg/1000mg
Batch number 1080604 LIMT15-0169-005
Condition Time % Drug Release
Medium: 0.1N HCl 05 Min 44 45
10 Min 78 83
15 Min 95 97
20 Min 101 98
30 Min 104 99
45 Min 108 100

Figure 2. Comparative In-vitro dissolution profile of reference product Vs test product in 0.1 N HCl for Metformin

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1:
S.No. Ingredients
Functional category Qty mg/Tablet
2.5/500 mg % w/w 2.5/850 mg % w/w 2.5/1000 mg % w/w
Intragranular Part
1 Metformin HCl Active Ingredient 500.00 86.96 850.00 86.91 1000.00 86.96
Binder Solution
2 Linagliptin Active Ingredient 2.50 0.43 2.50 0.26 2.50 0.22
3 Co-povidone Binding agent 47.50 8.26 80.75 8.26 95.00 8.26
4 Meglumine Stabilizing agent 6.00 1.04 10.20 1.04 12.00 1.04
5 Purified Water Solvent q.s -- q.s -- q.s --
Extragranular Part
6 Corn starch Disintegrant 12.50 2.17 23.55 2.41 27.50 2.39
7 Colloidal silicon dioxide Glidant 1.50 0.26 2.50 0.26 3.00 0.26
8 Magnesium Stearate Lubricant 5.00 0.87 8.50 0.87 10.00 0.87
Total weight of core tablets 575.00 100.00 978.00 100.00 1150.00 100.00
Film coating:
9 Opadry Orange* Film coating material 17.25 3.00 -- -- -- --
10 Opadry Orange* Film coating material -- -- 29.34 3.00 -- --
11 Opadry Pink$ Film coating material -- -- -- -- 34.50 3.00
12 Purified water Solvent q.s -- q.s -- q.s --
Total weight of tablets 592.25 -- 1007.34 -- 1184.50 --

Manufacturing Process:
1. Sifting: Sift milled Metformin HCl through # 20 mesh.
2. Dry Mix: Load Step 1 materials in to RMG and mix for 10 minutes at impeller 150 RPM and chopper off.
3. Binder Solution preparatin: Disperse Linagliptin in Purified water under stirring to form a uniform dispersion. To the above step-3 add co-povidone and meglumine, slowly under continuous strirring and stirr continuously to form a uniform dispersion.
4. Granulation: Perform Granulation using contents of step 2 and step 3.
5. Wet Milling: Mill Granules of step 4 through 8 mm screen.
6. Drying: Dry contents of step 5 in Rapid Drier at 50°C temperature until LOD reaches to 1.0% to 2.0%.
7. Sizing and Milling: Seive contents of step 6 through # 20 mesh and mill retentions through 1.50 mm untill all the material passed through # 20 mesh.
8. Extragranular Sifting:
a. Sift corn starch through # 30 mesh.
b. Sift Colloidal Silicon dioxide through # 30 mesh
c. Sift Magnesium stearate through # 60 mesh.
9. Lubrication:
a. Load contents of step 7 and step 8 (a & b) into blender and mix for 10 minutes.
b. Add contents of Step 8 (c) to contents of step 9 (a) and mix for 5 minutes.
10. Compression: Compress the above blend by using suitable tooling.
11. Film Coating: Coat the tablets of step 10 with film coating material.

Example 2:
S.No. Ingredients
Functional category Qty mg/Tablet
2.5/500 mg % w/w 2.5/850 mg % w/w 2.5/1000 mg % w/w
Intragranular Part
1 Metformin HCl Active Ingredient 500.00 86.96 850.00 86.91 1000.00 86.96
Binder Solution
2 Linagliptin Active Ingredient 2.50 0.43 2.50 0.26 2.50 0.22
3 hypromellose Binding agent 47.50 8.26 80.75 8.26 95.00 8.26
4 Meglumine Stabilizing agent 6.00 1.04 10.20 1.04 12.00 1.04
5 Purified Water Solvent q.s -- q.s -- q.s --
Extragranular Part
6 Corn starch Disintegrant 12.50 2.17 23.55 2.41 27.50 2.39
7 Colloidal silicon dioxide Glidant 1.50 0.26 2.50 0.26 3.00 0.26
8 Magnesium Stearate Lubricant 5.00 0.87 8.50 0.87 10.00 0.87
Total weight of core tablets 575.00 100.00 978.00 100.00 1150.00 100.00
Film coating:
9 Opadry Orange* Film coating material 17.25 3.00 -- -- -- --
10 Opadry Orange* Film coating material -- -- 29.34 3.00 -- --
11 Opadry Pink$ Film coating material -- -- -- -- 34.50 3.00
12 Purified water Solvent q.s -- q.s -- q.s --
Total weight of tablets 592.25 -- 1007.34 -- 1184.50 --

Manufacturing Process:
1. Sifting: Sift milled Metformin HCl through # 20 mesh.
2. Dry Mix: Load Step 1 materials in to RMG and mix for 10 minutes at impeller 150 RPM and chopper off.
3. Binder Solution preparatin: Disperse Linagliptin in Purified water under stirring to form a uniform dispersion. To the above step-3 add hypromellose and meglumine, slowly under continuous strirring and stirr continuously to form a uniform dispersion.
4. Granulation: Perform Granulation using contents of step 2 and step 3.
5. Wet Milling: Mill Granules of step 4 through 8 mm screen.
6. Drying: Dry contents of step 5 in Rapid Drier at 50°C temperature until LOD reaches to 1.0% to 2.0%.
7. Sizing and Milling: Seive contents of step 6 through # 20 mesh and mill retentions through 1.50 mm untill all the material passed through # 20 mesh.
8. Extragranular Sifting:
a. Sift corn starch through # 30 mesh.
b. Sift Colloidal Silicon dioxide through # 30 mesh
c. Sift Magnesium stearate through # 60 mesh.
9. Lubrication:
c. Load contents of step 7 and step 8 (a & b) into blender and mix for 10 minutes.
d. Add contents of Step 8 (c) to contents of step 9 (a) and mix for 5 minutes.
10. Compression: Compress the above blend by using suitable tooling.
11. Film Coating: Coat the tablets of step 10 with film coating material.
,CLAIMS:1. An immediate release pharmaceutical dosage form comprising:
a) Intra-granular portion contain Metformin or a pharmaceutically acceptable salt thereof.
b) binder solution contains a Linagliptin or a pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients contain Meglumine.
c) Extra-granular portion contain one or more pharmaceutically acceptable excipients.

2. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the binder solution is prepared by adding Linagliptin with binder agent with one or more pharmaceutically acceptable excipients.

3. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the
Process for preparation involves the following steps.
• Metformin HCl sifted and mixed dry,
• Binder solution prepared by mixing Linagliptin, co-povidone and Meglumine in water.
• Mix the binder solution and Metformin HCl.
• Milled and sieved the resultant mixture.
• Starch colloidal silicon dioxide and magnesium stated and added to the above mixture for lubrication.
• Lubricated mixture is punched with suitable tooling and optionally coated.

4. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the Meglumine is used as stabilizing agent.

5. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the
composition is prepared by wet granulation method.

6. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the composition is prepared by fluid bed process.

7. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the co-povidone used as binding agent.

8. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the corn starch used as disintegrant.

9. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the colloidal silicon dioxide used as glidants.

10. An immediate release pharmaceutical dosage form as claimed in claim 1, where in the magnesium stearate used as lubricant.