WO2025144125A1

WO2025144125A1 - Stable pharmaceutical composition with improved genotoxic impurity profile

Info

Publication number: WO2025144125A1
Application number: PCT/TR2023/051762
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2023-12-27
Filing date: 2023-12-27
Publication date: 2025-07-03
Anticipated expiration: 2026-06-27

Abstract

The present invention relates to a stable pharmaceutical formulation comprising linagliptin or pharmaceutically acceptable forms or derivatives thereof and at least one pharmaceutically acceptable excipient is obtained wherein the manufacturing method is direct compression method, wherein the composition is free of any nitrosamine impurity.

Description

STABLE PHARMACEUTICAL COMPOSITION WITH IMPROVED GENOTOXIC

IMPURITY PROFILE

Field Of The Invention

The present invention relates to a stable pharmaceutical composition comprising linagliptin or pharmaceutically acceptable forms or derivatives thereof and at least one pharmaceutically acceptable excipient manufactured using direct compression method, wherein the composition is free of any nitrosamine impurity.

Background Of The Invention

GLP-1 plays a role in reducing blood glucose levels by enhancing insulin release in response to glucose. Additionally, GLP-1 inhibits glucagon secretion, delays gastric emptying, and induces a feeling of satiety. The plasma half-life of GLP-1 is limited to a few minutes due to proteolytic degradation caused by the enzyme DPP-4. Inhibition of DPP-4 extends the plasma half-life of active GLP-1, leading to an increase in plasma insulin levels and a decrease in plasma glucose levels. As GLP-1 activity ceases, prolonging the half-life of GLP-1 through DPP-4 inhibitors poses little risk of hypoglycemia.

Linagliptin is a selective, competitive, orally administered, xanthine-based DPP-4 inhibitor with a 50% Inhibitor Concentration (IC50) of 1 nM. Linagliptin is primarily eliminated unchanged through feces, with renal excretion being a minor pathway at therapeutic doses. Therefore, linagliptin is well-suited for treating patients with renal impairment without requiring dose adjustment.

The chemical name of linagliptin is 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione.The empirical formula of linagliptin is C25H28N8O2 and its relative molecular mass is 408.87 mg/mole as a free base. The structural formula of linagliptin is shown in the Formula I.

Formula I It is a white to yellowish crystalline solid substance. It exhibits slight hygroscopicity, but the absorption of water does not alter its crystal modification.

Linagliptin has one chiral centre at the 3 -aminopiperidine moiety. The active substance corresponds to the R-enantiomer. Besides that, it substance simultaneously exists in two polymorphic forms, which are enantiotropic ally related and which reversibly convert into each other approximately at room temperature. The two polymorphic forms do not differ with regard to biopharmaceutical properties.

Linagliptin base and its pharmaceutically acceptable salts with the process for the preparation first have been described in EP1532149 numbered patent document by Boehringer Ingelheim Pharma for the treatment of diseases, such as, for example, type 1 diabetes, type 2 diabetes, adipositas, arthritis, and calcitonin-caused osteoporosis.

Linagliptin was first commercially authorized in U.S. Food&Drug Administration in May 2011. The medicinal product is currently marketed in the form of immediate -release film-coated tablets under the trade name of TRAJENTA® at the strength of 5 mg per tablet. It can be used as monotherapy or in combination with other common antidiabetic medications including metformin, sulfonylurea, pioglitazone or insulin.

Linagliptin, with high solubility in aqueous media (> 1 mg/ml) across the entire physiological pH range, was rapidly absorbed, after oral administration of a 5 mg dose or multiple doses to both healthy volunteers and patients, with peak plasma concentrations (median T_max) occuring 1.5 hours post-dose. However, the absolute bioavailability of linagliptin is approximately 30%.

In the state of the art there are many patents/patent applications which are summarized below.

EP2023902 relates to pharmaceutical compositions of linagliptin and its preparations for the treatment of diabetes mellitus. The patent document is specifically disclosed to qualitative properties of the prepared pharmaceutical composition comprising mannitol and pregelatinized starch are used as diluent, copovidone is used as binder, com starch is used as disintegrant and magnesium stearat is used as lubricant. It also disclosed the process for the preparation of a pharmaceutical composition in which wet granulation is used. Further, it specifies that excipients like microcrystalline cellulose and lactose were observed as being incompatible with DPP-IV inhibitors. EP2023902 has divisional applications such as EP2277509, EP2283819 and EP2910241. These divisional applications are also disclosed to a pharmaceutical composition comprising linagliptin, a first diluent mannitol, a second diluent pregelatinized starch, a binder copovidone, a disintegrant corn starch, and a lubricant magnesium stearate. It is also emphasized that should be avoided from microcrystalline cellulose use which causes oxidation and negative impacts on impurity profile.

EP1852108 relates to a pharmaceutical composition comprising linagliptin as an active substance and at least one pharmaceutical composition in which mannitol and pregelatinized starch are used as diluent, copovidone is used as binder, corn starch and crospovidone are used as disintegrant, colloidal silicon dioxide is used as glidant and magnesium stearate is used as lubricant.

EP2882424 relates to a stable pharmaceutical composition comprising linagliptin or a pharmaceutically acceptable salt thereof as active ingredient, mannitol, copovidone, and magnesium stearate, wherein the mannitol is present in an amount of 90 to 95 % by weight, based on the pharmaceutical composition, and the pharmaceutical composition is prepared by direct compression.

EP3311803 relates to a pharmaceutical composition comprising linagliptin, mannitol, copovidone, and magnesium stearate, wherein the pharmaceutical composition is prepared by direct compression.

W02014080384 relates to a pharmaceutical composition comprising linagliptin and one or more pharmaceutically acceptable excipients, wherein said composition is free of one or more of mannitol, corn starch, copovidone and magnesium stearate.

W02014009970 relates to an amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, wherein said acceptable carrier comprises one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.

EP3801539 relates to a solid oral pharmaceutical formulation comprising linagliptin or a pharmaceutically acceptable salt thereof, wherein the composition is free of microcrystalline cellulose, croscarmellose sodium and stearates.

EP3723761 relates to a pharmaceutical solid oral dosage form comprising linagliptin as an active agent and at least one binder in which the weight ratio of linagliptin to povidone used as binder is between 0.1 and 6.0, preferably is between 0.5 and 2.0. EP2853257 relates to a pharmaceutical formulation comprising linagliptin or pharmaceutically acceptable salt thereof, croscarmellose sodium and at least one other pharmaceutically acceptable excipient.

In the state of the art, pharmaceutical compositions comprising DPP-4 inhibitor with primary or secondary amino group show incompatibilities, degradation problems, or extraction issues when used several common excipients, including microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose. Linagliptin has a primary amine group on its chemical structure. However, although linagliptin itself is highly stable, it can potentially react with various excipients employed in solid dosage forms or impurities within those excipients. This is particularly applicable in tight contact provided in tablets, where the amino group in linagliptin may interact with reducing sugars, other reactive carbonyl groups, and carboxylic acid functional groups formed on the surface of oxidative excipients such as microcrystalline cellulose.

According to this, pharmaceutical impurities, including genotoxic impurities, class of compounds having chemical structure with nitroso group bonded to amine, can form during storage conditions or excipient interactions, such as oxidative excipients with active substance having amino group. Genotoxic impurities are classified as probable human carcinogens (substances that could cause cancer) and should be quantified at trace levels as much as possible to ensure that their concentrations do not pose any harm for human consumption.

Based on the patent or patent applications provided above, the degradation and/or impurity formation related to genotoxic impurities resulting from the reaction between the linagliptin, having primary amino group, and an oxidative excipient like microcrystalline cellulose in any pharmaceutical composition is not disclosed.

Therefore, the inventors of the present invention have developed a stable pharmaceutical composition comprising linagliptin or its pharmaceutically acceptable salt/derivatives thereof and an oxidative excipient manufactured by using direct compression with improved stability profiles comprising genotoxic impurities.

Summary Of The Invention

The object of this invention is to develop a stable pharmaceutical composition comprising a therapeutically effective amount of linagliptin or a pharmaceutically acceptable salt/derivatives thereof and at least one pharmaceutically acceptable excipient manufactured using direct compression method.

The object of the present invention is to provide a stable pharmaceutical composition comprising linagliptin in crystalline form. Preferably, the crystalline form is present as a mixture of two polymorphic forms A and B .

According to the literature, the primary amine group in linagliptin can lead to the formation of genotoxic impurities, such as N-nitrosodimathylamine (NDMA), through reactions with reducing sugars, other reactive carbonyl groups, and carboxylic acid functional groups formed on the surface of microcrystalline cellulose due to oxidation.

Another object of the present invention relates to a pharmaceutical composition comprising linagliptin and at least one pharmaceutically acceptable excipient wherein the composition comprises an oxidative excipient such as microcrystalline cellulose.

Another objective of the present invention is to provide a pharmaceutical composition that exhibits improved stability and mitigates the presence of genotoxic impurities resulting from incompatibility between linagliptin and an oxidative excipient, such as microcrystalline cellulose.

Another objective of the present invention is to provide a stable pharmaceutical composition comprising linagliptin, an oxidative excipient and at least one pharmaceutically acceptable excipient, manufactured using direct compression method.

Detailed Description Of The Invention

The present invention provides a stable pharmaceutical composition comprising a therapeutically effective amount of linagliptin in crystalline form and at least one pharmaceutically acceptable excipient is manufactured by using direct compression method.

In the preferred embodiment, linagliptin is in the mixture of two polymorphic form (“Form A” and “Form B”) which are enantiotropically related and which reversibly convert into each other approximately at room temperature. However, even if there is a conversion, any crystal modification is not observed during the uptaking of the water. Thus, these polymorphic forms make no difference in physicochemical properties (stability, solubility and intrinsic dissolution properties) and have no impact on bioavailability. In the present invention, linagliptin is present as a low-dose drug that is constituted less than 4% weight by the total weight of the composition.

In the patent document numbered as EP2023902B1 declares that DPP-4 inhibitor with primary or secondary amino group show incompatibilities, degradation problems, or extraction issues when used several common excipients, including microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose.

Linagliptin is a primary amine group in its chemical structure, where the amino group has the potential to the formation of genotoxic impurities by interacting with reducing sugars, other reactive carbonyl groups, and carboxylic acid functional groups that form on the surface of oxidative excipients, such as microcrystalline cellulose.

N-Nitrosamine compounds refer to molecules containing the (N-NO) nitroso functional group. N-nitroso compounds constitute a significant category of carcinogens, with N-nitrosamines being part of this group. Nitrosamine impurities are considered likely to demonstrate human mutagenicity, teratogenicity, and carcinogenicity.

According to ICH M7 (Rl), Nitrosamine impurities are classified as Class 1 Genotoxic impurities, recognized for their mutagenic and carcinogenic. Thus, in the present embodiment, the aim is to investigate the potential presence of nitrosamine impurities at elevated levels resulting from interaction between active substance and an oxidative excipient.

In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising linagliptin by using direct compression method wherein provided for the manufacture of tablets containing the active ingredient, diluents, binder, lubricant(s) and glidant(s) selected as to be the most suitable ones with respect to the intended form of administration.

In a preferred embodiment, the pharmaceutical composition comprises at least one diluent can be selected from the group consisting of dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, the diluent is mannitol and microcrystalline cellulose or a mixture thereof, more preferably is a mixture thereof. In a preferred embodiment, the pharmaceutical composition comprises binder can be selected from the group consisting of hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is pregelatinized starch.

In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant can be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof. Preferably, the lubricant is magnesium stearate.

In a preferred embodiment, the pharmaceutical composition comprises at least one glidant can be selected from the group consisting of colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof. Preferably, the glidants are colloidal silicon dioxide and talc or a mixture thereof.

The proposed embodiment based on the invention provides a stable pharmaceutical composition wherein the amounts in w/w% of the total composition are as stated in Table 1 below.

Table 1: Unit Formula of Example 1

Further in a preferred embodiment, the process for the preparation of a pharmaceutical composition manufactured by using direct compression, including the steps of: a) Linagliptin, talc, colloidal silicon dioxide, and the specified amount of microcrystalline cellulose were screened through a proper sieve and stirred, b) The rest of the microcrystalline cellulose, mannitol and starch were screened through a proper sieve, added to the powder blend prepared in Step (a) and stirred. c) Magnesium stearate was screened through a proper sieve, added to the powder blend prepared in Step (b) and stirred to obtain a uniform final blend. d) Tablet compression was performed with the final blend in Step (c).

Further, the obtained tablets were subjected to nitrosamine impurity analysis using validated analytical methods to identify and quantify several nitrosamine impurities.

According to the literature, various nitrosamine impurities could theoretically be present in drug products, including nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N- nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N- nitrosodiisopropylamine (NDIPA), Nnitrosodibutylamine (NDBA), and N- nitrosomethylphenylamine (NMPA). These impurities are named as common impurities that can be observed in the pharmaceutical formulations regardless of the type of active ingredient.

Thus, nitrosamine impurities originated due to linagliptin chemical structure by an oxidation reaction due to environmental conditions during manufacturing and/or incompatibility between excipients which have oxidative nature.

One of the most probable nitrosamine impurity that could be observed in pharmaceutical compostions comprising linagliptin as active ingredient is 4-nitrosomethylaminopyridine.

Based on the information above, in the preferred embodiment, specifically, N- Nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosomethylamino butyric acid (NMBA), N-nitrosodibutylamine (NDBA), N-Nitrosomethylphenylamine (NMPA) and 4-nitrosomethylaminopyridine impurities were examined, and the results are presented in Table 2 below.

Table-2: The result of nitrosamine impurity analysis of Example 1

Another technical investigation on nitrosamine impurity content in Example 1 is related with the behaviour of the formulation under stability conditions, particularly under the accelerated stability conditions at 6^th month. Accelerated stability conditions are; 40°C±0.5°C, 75%±5% RH.

Table-3: The result of nitrosamine impurity analysis of Example 1 under accelerated stability conditions at 6^th month

According to all results of the impurity analysis, in the embodiment of the present invention, a stable linagliptin formulation along with at least one pharmaceutically acceptable excipient designed wherein; the formulation is manufactured by using direct compression, and the formulation comprises microcrystalline cellulose as at least one oxidative nature excipient.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A stable pharmaceutical formulation comprising linagliptin or pharmaceutically acceptable salts or derivatives thereof and at least one pharmaceutically acceptable excipient, wherein; the formulation is manufactured by using direct compression, and the formulation comprises microcrystalline cellulose as an oxidative nature excipient.

2. A stable pharmaceutical formulation according to claim 1, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from binders, glidants, lubricants and mixtures thereof.

3. A stable pharmaceutical formulation according to claim 2, wherein the composition comprises binder selected from hypromellose, low -substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol and mixtures thereof.

4. A stable pharmaceutical formulation according to claim 3, wherein the binder is pregelatinized starch.

5. A stable pharmaceutical formulation according to any one of the claim 2, wherein the composition comprises glidant selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.

6. A stable pharmaceutical formulation according to claim 5, wherein the glidant is a mixture of talc and colloidal silicondioxide.

7. A stable pharmaceutical formulation according to any one of the claim 2, wherein the composition comprises lubricant selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof.

8. A stable pharmaceutical formulation according to claim 7, wherein the lubricant is magnesium stearate.

9. A direct compression method for the manufacturing of a pharmaceutical formulation according to any one of the preceding claims, wherein the process comprising the steps of; a) Linagliptin, talc, colloidal silicon dioxide, and the specified amount of microcrystalline cellulose are screened through a proper sieve and stirred, b) The rest of the microcrystalline cellulose, mannitol and starch are screened through a proper sieve, added to the powder blend prepared in Step (a) and stirred. c) Magnesium stearate is screened through a proper sieve, added to the powder blend prepared in Step (b) and stirred to obtain a uniform final blend. d) Tablet compression is performed with the final blend in Step (c).