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WO2022023213A1 - Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine - Google Patents

Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine Download PDF

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Publication number
WO2022023213A1
WO2022023213A1 PCT/EP2021/070703 EP2021070703W WO2022023213A1 WO 2022023213 A1 WO2022023213 A1 WO 2022023213A1 EP 2021070703 W EP2021070703 W EP 2021070703W WO 2022023213 A1 WO2022023213 A1 WO 2022023213A1
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Prior art keywords
metformin
dosage form
acceptable salt
pharmaceutical dosage
physiologically acceptable
Prior art date
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Ceased
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PCT/EP2021/070703
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English (en)
Inventor
Luka ŽNIDERŠIC
Luka ŠENICA
Alen GABRIC
Sergeja Bombek
Klemen KORASA
Matej REPIC
Gašper VRHUNC
Žiga HODNIK
Ilija BUZAR
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KRKA dd
Original Assignee
KRKA dd
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Publication date
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Priority to EP21749796.5A priority Critical patent/EP4188352A1/fr
Publication of WO2022023213A1 publication Critical patent/WO2022023213A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the invention relates to a pharmaceutical composition or dosage form of metformin or a physi ologically acceptable salt thereof, possibly in combination with one or more other active pharmaceutical ingredients.
  • the pharmaceutical composition or dosage form has a content of N-nitroso dimethylamine (NDMA) below 48 ppb.
  • NDMA N-nitroso dimethylamine
  • the invention further relates to analytical methods for determining the content of NDMA and dimethylamine (DMA). These methods are suitable for monitoring the correlation be tween DMA that is entrained as an impurity along with metformin used as staring material and the NDMA content of the final pharmaceutical composition or dosage form containing metformin.
  • Metformin is an antidiabetic agent that has become one of the most widely used drugs in the treatment of type 2 diabetes mellitus (T2DM) since its approval in the United Kingdom in 1958 and in the United States in 1995, with doses ranging from 500 to 2,000 mg/day. It is the first-line therapy for patients with T2DM according to the American Diabetes Association/European Association for Study of Diabetes guidelines. Metformin works by decreasing intestinal glucose absorption, improving periph eral glucose uptake, lowering fasting plasma insulin levels and increasing insulin sensitivity, which re sult in a reduction of blood glucose concentrations without causing overt hypoglycemia.
  • Metformin is marketed in immediate-release formulations and extended-release formulations and is available in several products in combination with other active pharmaceutical ingredients, espe cially antidiabetic agents.
  • N-nitrosamines are gen erally formed when certain amines react with suitable nitrosating agents.
  • the main sources tend to be tobacco, cured meats such as bacon, fermented foods such as beer and cheese, shampoo and cleansers, and detergents and pesticides.
  • NDMA formation occurs when during cooking nitrite preservatives react with amines and with amino acids that are contained in the meat.
  • NDMA is classified as a group 2A carcinogen, or “probably carcinogenic to humans,” according to the International Agency for Research on Cancer. This means that there is no direct evidence that NDMA causes cancer in humans, but it is likely that NMDA is cancerogenic because it has caused cancer in animals. On the basis of animal studies, both FDA and Health Canada have set an acceptable intake limit for NDMA of 0.096 pg per day.
  • N-nitrosamine contaminants are potential carcinogens
  • regulatory agencies have deemed these formulations unsuitable for commercialization over the counter (OTC).
  • OTC over the counter
  • Valsartan was recalled in July 2018, followed by irbesartan in October and by losartan in November.
  • Irbesartan and losartan are another two ARBs and their formulations were found to also contain NDMA and the related compound N-nitroso diethylamine (NDEA).
  • NDEA N-nitroso diethylamine
  • NDMA has also been found in metformin, an antidiabetic agent that is taken by over 15.8 million people worldwide. On May 28, 2020 FDA recommended that five companies supplying the drug should recall their products.
  • WO 2012/031124 A2 relates to solid, semisolid, or liquid formulations comprising water soluble antioxidants that prevent or reduce formic acid and/or formyl species generation in the dos-age form during the manufacturing process and/or during shelf-life storage.
  • the formulations of the present in vention prevent or reduce formation of N-formyl impurities (and gelatin crosslinking) during the man ufacturing process and/or during shelf-life storage.
  • US 8,414,921 B2 relates to pharmaceutical compositions comprising fixed-dose combinations of a dipeptidyl peptidase-4 inhibitor and metformin, methods of preparing such pharmaceutical compo sitions, and methods of treating Type 2 diabetes with such pharmaceutical compositions.
  • US2011/0021634 Al discloses a process for reducing dimethylamine content in metformin hy drochloride.
  • the process comprises: (a) providing metformin hydrochloride having dimethylamine con tent more than 15 ppm; (b) pulverizing the metformin hydrochloride; (c) slurrying the metformin hy drochloride in one or more C1-C4 alcohol solvents; and (d) isolating the metformin hydrochloride.
  • Ex amples 1 and 2 of US2011/0021634 Al disclose the preparation of metformin hydrochloride.
  • the prep aration process includes various purification steps of metformin hydrochloride, which inter alia require the use of water and methanol and purging with nitrogen gas.
  • the process further includes grinding the metformin hydrochloride in the presence of methanol, which could lead to residues of methanol in the final metformin hydrochloride. Such residues would be undesirable, particularly in a substance for phar maceutical application, due to the toxicity of methanol.
  • the entire process results in metformin hydro chloride with a DMA content of less than 5 ppm, but is comparatively laborious.
  • US2011/0021634 A 1 does not relate to reducing the NDMA content of pharmaceutical compositions or dosage forms com prising metformin or a physiologically acceptable salt thereof.
  • compositions and pharmaceutical dos age forms that have improved safety, preferably because they do not contain excessive quantities of NMDA, and that can be prepared in an economic manner on industrial scale.
  • metformin is most labile in alkaline and oxidative environments.
  • ammonia and DMA are formed, which can react by one of the possible reaction pathways to form N,N-dime- thylhydrazine. The latter can then be oxidized to NDMA.
  • DMA can react to NDMA in alkaline envi ronment even in the simultaneous presence of nitrite ions and formaldehyde.
  • DMA can be evaporated from metformin starting material and from compositions containing metformin, respectively. It has been found that grinding of metformin is possible under dry conditions, i.e. without solvent, resulting in a reduced content of DMA.
  • the final product may contain NDMA in contents of less than the permitted limit of 48 ppb.
  • active pharmaceutical ingredients e.g., sitagliptin, vildagliptin, linagliptin
  • the finished product comprising metformin or physiologically acceptable salt thereof according to the present invention, prepared by technology comprising drying and/or milling of metformin before and/or during the manufacture of the finished product and/or the addition of organic acid to the pharma ceutical composition, ensures an NDMA content below the safe limit of 48 ppb or 48 ng NDMA / 1 g metformin hydrochloride during the shelf life, as determined by the GC-MS method according to the invention as describe herein.
  • a first aspect of the invention relates to a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof and having a content of N-nitroso dimethylamine of not more than 48 ppb, relative to the total weight of metformin in the pharmaceutical dosage form.
  • the invention relates to a pharmaceutical composition and pharmaceutical dosage forms of metformin hydrochloride or combinations of metformin hydrochloride with any other pharma ceutically active ingredient that provides an NDMA (N-nitroso dimethylamine) content below the per missible limit of 48 ppb.
  • NDMA N-nitroso dimethylamine
  • a pharmaceutical dosage form is any administration unit that is suitable to administer a therapeutically effective amount of metformin or a physiologically ac ceptable salt thereof to a subject in need thereof.
  • the pharmaceutical dosage form is solid, preferably a capsule, tablet, sachet, or the like.
  • all percentages are weight percent and refer to the total weight of the pharmaceutical dosage forms. Content of DMA in metformin or pharmaceutically accepta ble salt thereof is reported with respect to the total weight of metformin active ingredient. Content of NDMA and DMA in pharmaceutical dosage forms, on the other hand, are reported with respect to the total weight of metformin in the pharmaceutical dosage forms.
  • the pharmaceutical dosage form is typically devoted for administering a therapeutically effec tive amount of metformin (ATC A10BA02) or a physiologically acceptable salt thereof to a subject in need thereof.
  • the dose of metformin or a physiologically acceptable salt thereof that is contained in the pharmaceutical dosage form preferably amounts to 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg, in each case expressed as equivalent dose relative to metformin hydrochloride.
  • Metformin can generally be prepared by any known process such as the processes described in US20110021634, W02016059507, IN201621016063, IN2010MUM1409 and the examples provided below.
  • preparation of the pharmaceutical composition or pharmaceutical dosage form ac cording to the invention involves
  • the pharmaceutical dosage form contains not more than 45 ppb N- nitroso dimethylamine; preferably not more than 40 ppb, more preferably not more than 35 ppb, still more preferably not more than 30 ppb, yet more preferably not more than 25 ppb, even more preferably not more than 20 ppb, most preferably not more than 15 ppb, and in particular not more than 10 ppb N- nitroso dimethylamine, in each case relative to the total weight of metformin incorporated in the phar maceutical dosage form.
  • the content of N-nitroso dimethylamine is determined according to the method of the invention as described herein, preferably as described in the experimental section.
  • DMA EP impurity F
  • is limited to 0.05 wt.-% ( 500 ppm) in metformin or a physiologically acceptable salt thereof and is controlled by a limit HPLC test.
  • the pharmaceutical dosage form according to the invention has a content of dime- thylamine of not more than 200 ppm, relative to the total weight of metformin in the pharmaceutical dosage form.
  • the pharmaceutical composition or pharmaceutical dosage form according to the in vention is preferably, the pharmaceutical composition or pharmaceutical dosage form according to the in vention
  • - comprises at least metformin or a physiologically acceptable salt thereof with a DMA content (di- methylamine; EP impurity F) lower than 200 ppm, and/or
  • - comprises a physiologically acceptable acid
  • metformin starting material comprising less than 200 ppm of DMA.
  • the pharmaceutical composition or pharmaceutical dosage form according to the in vention is preferably, the pharmaceutical composition or pharmaceutical dosage form according to the in vention
  • - comprises at least metformin or a physiologically acceptable salt thereof with a DMA content (di- methylamine; EP impurity F) lower than 100 ppm, and/or
  • - comprises a physiologically acceptable acid
  • metformin starting material comprising less than 100 ppm of DMA.
  • the pharmaceutical dosage form according to the invention contains not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the total weight of metformin incorporated in the pharmaceutical dosage form.
  • the content of dimethylamine is determined according to the method of the invention as described herein, preferably as described in the experimental section.
  • the pharmaceutical dosage form according to the invention contains a physiologically acceptable acid.
  • the acid in pure form under ambient conditions is a solid, preferably a crystalline material.
  • the acid is an organic acid or an inorganic acid.
  • the acid is not particularly limited and may contain other functional groups such as hydroxyl groups, amino groups, and the like.
  • the acid has an acidic functional group selected from the group consisting of carbox ylic acid functional groups, vinylogous carboxylic acid functional groups, and sulfonic acid functional groups.
  • the acid has a pKA value within the range of from 0.5 to 6.0.
  • the acid is multiprotonic, preferably at least one of the PK A values of the acidic functional groups is within this range, preferably the PK A value of the most acidic functional group (typically also referred to as PK AI ).
  • the acid has a pKA value within the range of 1.0 ⁇ 0.5, or 1 5 ⁇ 1.0, or 1.5 ⁇ 0.5 or 2.0 ⁇ 1.5, or 2.0 ⁇ 1.0, or 2.0 ⁇ 0.5 or 2.5 ⁇ 2.0, or 2.5 ⁇ 1.5, or 2.5 ⁇ 1.0, or 2.5 ⁇ 0.5 or 3.0 ⁇ 2.5, or 3.0 ⁇ 2.0, or 3.0 ⁇ 1.5, or 3.0 ⁇ 1.0, or 3.0 ⁇ 0.5 or 3.5 ⁇ 2.5, or 3.5 ⁇ 2.0, or 3.5 ⁇ 1.5, or 3.5 ⁇ 1.0, or 3.5 ⁇ 0.5 or 4.0 ⁇ 2.0, or 4.0 ⁇ 1.5, or 4.0 ⁇ 1.0, or 4.0 ⁇ 0.5 or 4.5 ⁇ 1.5, or 4.5 ⁇ 1.0, or 4.5 ⁇ 0.5 or 5.0 ⁇ 1.0, or 5.0 ⁇ 0.5 or 5.5 ⁇ 0.5.
  • the acid is a monoprotonic acid or a multiprotonic acid.
  • the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, ascorbic acid, methylsulfonic acid, benzene sulfonic acid, toluene sulfonic acid, and sulfamic acid; pref erably ascorbic acid, succinic acid, oxalic acid, maleic acid or sulfamic acid; more preferably succinic acid, ascorbic acid, or sulfamic acid.
  • the content of the acid is within the range of from 0.01 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form; preferably 0.01 to 20 wt.-%, relative to the total weight of the pharmaceutical dosage form; more preferably 0.01 to 10 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the content of the acid is within the range of 0.10 ⁇ 0.05 wt.-%, or 0.15 ⁇ 0.10 wt.-%, or 0.15 ⁇ 0.05 wt.-%, or 0.20 ⁇ 0.15 wt.-%, or 0.20 ⁇ 0.10 wt.-%, or 0.20 ⁇ 0.05 wt.-%, or
  • 0.35 ⁇ 0.25 wt.-% 0.35 ⁇ 0.20 wt.-%, or 0.35 ⁇ 0.15 wt.-%, or 0.35 ⁇ 0.10 wt.-%, or 0.35 ⁇ 0.05 wt.-%, or
  • 0.40 ⁇ 0.35 wt.-% or 0.40 ⁇ 0.30 wt.-%, or 0.40 ⁇ 0.25 wt.-%, or 0.40 ⁇ 0.20 wt.-%, or 0.40 ⁇ 0.15 wt.-%, or
  • 0.45 ⁇ 0.25 wt.-% or 0.45 ⁇ 0.20 wt.-%, or 0.45 ⁇ 0.15 wt.-%, or 0.45 ⁇ 0.10 wt.-%, or 0.45 ⁇ 0.05 wt.-%, or
  • 0.50 ⁇ 0.45 wt.-% or 0.50 ⁇ 0.40 wt.-%, or 0.50 ⁇ 0.35 wt.-%, or 0.50 ⁇ 0.30 wt.-%, or 0.50 ⁇ 0.25 wt.-%, or
  • the pharmaceutical dosage form is prepared by granulation and comprises an intra- granular phase as well as an extragranular phase.
  • the acid more preferably essentially the total amount of the acid, is contained in the intragranular phase, preferably together with the metformin or the physiologically acceptable salt thereof, preferably in a homogenous intimate mix ture.
  • the acid more preferably essentially the total amount of the acid, is contained in the extragranular phase, whereas the metformin or the physiologically acceptable salt thereof is contained in the intragranular phase.
  • the pharmaceutical dosage form comprises a fdm coating and the acid, more preferably essentially the total amount of the acid, is contained in the fdm coating, whereas the metformin or the physiologically acceptable salt thereof is contained in the core that is encapsulated by the fdm coating, preferably in the intragranular phase of said core.
  • metformin starting material for incorporation into a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof, wherein the content of metformin or the physiologically acceptable salt thereof is at least 99.0 wt.-%, relative to the total weight of the metformin starting material; and wherein the metformin starting material has a content of dime- thylamine of not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the total weight of the metformin starting material.
  • metformin starting material for incorporation into a pharmaceuti cal dosage form comprising metformin or physiologically acceptable salt thereof is present as a powder having a median diameter D(50), determined by laser diffraction analysis, of not more than 200 mih; preferably not more than 100 pm;.
  • metformin or the physiologically acceptable salt thereof as contained in the pharma ceutical dosage form or in metformin starting material is a solid, crystalline or amorphous material. It may comprise any polymorph, solvate, cocrystal, and the like of metformin or the physiologically ac ceptable salt thereof.
  • the physiologically acceptable salt of metformin is the hydrochloride.
  • the content of metformin or the physiologically acceptable salt thereof is within the range of from 60 to 90 wt.-%, relative to the total weight of the pharmaceutical dosage form and the weight of metformin or the physiologically acceptable salt thereof.
  • the content of metformin or the physiologically acceptable salt thereof is within the range of 65 ⁇ 5 wt.-%, or 70 ⁇ 10 wt.-%, or 70 ⁇ 5 wt.-%, or 75 ⁇ 15 wt.-%, or 75 ⁇ 10 wt.-%, or 75 ⁇ 5 wt.-%, or 80 ⁇ 15 wt.-%, or 80 ⁇ 10 wt.-%, or 80 ⁇ 5 wt.-%, or 85 ⁇ 10 wt.-%, or 85 ⁇ 5 wt.- %, in each case relative to the total weight of the pharmaceutical dosage form and the weight of metfor min or the physiologically acceptable salt thereof.
  • the pharmaceutical dosage form according to the invention contains one or more binders/diluents.
  • the one or more binders/diluents independently of one another are selected from the group consisting of sucrose, lactose, starch, cellulose, cellulose ethers (preferably selected from hydrox- yethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose), sugar alcohols (prefera bly selected from xylitol, sorbitol, and mannitol), gelatin, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers and polyethylene glycol.
  • the total content of the one or more binders/diluents is within the range of 1.0 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention contains one or more lubricants.
  • the one or more lubricants independently of one another are selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, and talk.
  • the total content of the one or more lubricants is within the range of 0.1 to 5.0 wt- %, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention contains an additional active pharmaceutical ingredient other than metformin or the physiologically acceptable salt thereof.
  • the additional active pharmaceutical ingredient is an antidiabetic agent.
  • the additional active pharmaceutical ingredient is selected from the group consisting of thiazolidinediones, such as pioglitazone or rosiglitazone; sulfonylureas, such as gliclazide, glimepiride or gluburide; meglitinides, such as repaglinide or nataglinide; dipeptidyl peptidase-4 (DPP- 4) inhibitors, such as sitagliptin, vildagliptin, linagliptin or saxagliptin; SGLT-2 inhibitors, such as dapagliflozin, canagliflozin, empagliflozin, and the physiologically acceptable salts of any of the fore going.
  • thiazolidinediones such as pioglitazone or rosiglitazone
  • sulfonylureas such as gliclazide, glimepiride or gluburide
  • the additional active pharmaceutical ingredient is selected from the group consisting sitagliptin, vildagliptin, linagliptin, dapagliflozin, canagliflozin and empagliflozin, and the physiologi cally acceptable salts of any of the foregoing.
  • the content of the additional active pharmaceutical ingredient is within the range of from 0.5 to 15 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to the invention is a tablet.
  • the pharmaceutical dosage form according to the invention is film coated.
  • suitable materials for film coating are known to the skilled person.
  • the material for film coating is selected from water soluble polymers such as polyvinylalcohol, hydroxypropylmethylcellulose, and the like.
  • the material for film coating is not an enteric coating material.
  • the pharmaceutical dosage form according to the invention has been prepared by direct compression.
  • the pharmaceutical dosage form according to the invention has been prepared by granulation.
  • the pharmaceutical dosage form according to the invention has been prepared by dry granulation.
  • the pharmaceutical dosage form according to the invention has been prepared by wet granulation.
  • Another aspect of the invention relates to a process for the preparation of a pharmaceutical dosage form according to the invention as described above, the process comprising the steps of:
  • the manufacture of a pharmaceutical dosage form according to the invention preferably com prises drying and/or grinding metformin or a physiologically acceptable salt thereof, wet granulation, tableting and tablet coating (film coating).
  • Steps (ii), (iii), (v), (vi), (vii) and (ix) of the process according to the invention are optional.
  • the process according to the invention comprises steps (i), (iv), and (viii); or (i), (ii), (iv), and (viii); or (i), (iii), (iv), and (viii); or (i), (iv), (v) and (viii); or (i), (iv), (vii) and (viii); or (i), (iv), (viii) and (ix); or (i), (ii), (ii), (iv), (v), and (viii); or (i), (ii), (iv), (v) and (viii); or (i), (ii), (iv), (v) and (viii); or (i), (ii), (iv), (vii) and (viii); or (i), (ii), (iv), (viii), and (ix); or (i), (ii), (ii
  • Steps (i) to (ix) of the process according to the invention may be performed simultaneously or consecutively, continuously or batchwise.
  • steps (i) to (ix) are performed in numerical order, whereas it is contemplated that consecutive steps may by performed simultaneously or partially simul taneously.
  • Step (i) of the process according to the invention involves providing metformin or a physiolog ically acceptable salt thereof.
  • Step (i) contemplates chemical synthesis of metformin or a physiologically acceptable salt thereof from suitable starting materials.
  • a commercially available metfor min or a physiologically acceptable salt thereof may be provided in step (i).
  • metformin com prising less than 200 ppm of DMA is provided.
  • step (ii) of the process according to the invention involves grinding the metformin or physiologically acceptable salt thereof thereby obtaining ground metformin or physiologically accepta ble salt thereof.
  • step (ii) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • the ground metformin or physiologically acceptable salt thereof ob tained in step (ii) has a median diameter D(50), determined by laser diffraction analysis, of not more than 200 pm; preferably not more than 100 pm.
  • step (iii) of the process according to the invention involves subjecting the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physio logically acceptable salt thereof.
  • step (iii) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.
  • step (iii) is performed in a fluid bed dryer or drying chamber.
  • step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C, more preferably of at least 70°C.
  • Step (iv) of the process according to the invention involves mixing the metformin or physiolog ically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, or the dried metformin or physiologically acceptable salt thereof, with one or more excipients, and optionally with one or more additional active pharmaceutical ingredients, thereby obtaining a first mixture.
  • step (iv) is performed under standard conditions known to the skilled person by means of tech nical equipment that is known to the skilled person as well and that is commercially available.
  • the one or more excipients that are employed in step (iv) are selected from binders, fillers, diluents, disintegrants and the like, preferably binders/diluents as defined above.
  • the one or more excipients form the intragran- ular phase of the pharmaceutical dosage form together with the metformin or physiologically acceptable salt thereof and optionally together with the additional active pharmaceutical ingredient.
  • step (v) of the process according to the invention involves granulating the first mixture thereby obtaining a granulate.
  • step (v) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • step (v) is performed as wet granulation by granulating the first mixture with a granulation fluid, optionally containing one or more excipients, and optionally containing one or more addi tional active pharmaceutical ingredients.
  • a granulation fluid optionally containing one or more excipients, and optionally containing one or more addi tional active pharmaceutical ingredients.
  • Suitable granulation fluids involve water, acetone and alcohols, preferably ethanol, or any mixture thereof.
  • step (vi) of the process according to the invention involves drying the granulate thereby obtaining a dried granulate.
  • step (vi) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • step (vii) of the process according to the invention involves (vii) mixing the granulate or the dried granulate with one or more excipients, and optionally with one or more additional active pharmaceutical ingredients, thereby obtaining a second mixture.
  • step (vii) is performed un der standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • the one or more excipients, and optionally the one or more additional active pharmaceutical ingredients form the extragranular phase of the phar maceutical dosage form.
  • the one or more excipients that are employed in step (vii) are selected from binders, fdlers, diluents, disintegrants and the like, preferably lubricants as defined above.
  • the excipients em ployed can have more functions simultaneously, e.g. microcrystalline cellulose can act as a diluent, binder or disintegrant.
  • Step (viii) of the process according to the invention involves compressing the first mixture, the granulate, the dried granulate, or the second mixture thereby obtaining a compressed core.
  • step (viii) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • step (ix) of the process according to the invention involves film coating the compressed core by applying a liquid coating composition.
  • step (ix) is performed under standard condi tions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.
  • the liquid coating composition employed in step (ix) preferably comprises a coating material selected from water soluble polymers such as polyvinylalcohol, hydroxypropylmethylcellulose, and the like.
  • the coating material is not an enteric coating material.
  • the liquid coating compositions comprises at least one other active ingredient.
  • step (a) among the one or more excipients employed in step (iv);
  • step (b) among the one or more excipients employed in step (vii);
  • Another aspect of the invention relates to a pharmaceutical dosage form obtainable by the pro cess according to the invention as described above.
  • the diabetes is type 2 diabetes mellitus (T2DM).
  • the pharmaceutical dosage form according to the invention is for oral administration; preferably once daily, twice daily or thrice daily.
  • Another aspect of the invention relates to a process for the preparation of a metformin starting material according to the invention as described above, the process comprising the steps of:
  • step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.
  • step (iii) is performed in a fluid bed dryer or drying chamber.
  • step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C.
  • Another aspect of the invention relates to a metformin starting material that is obtainable by the process according to the invention as described above.
  • GC-MS method for may be used for the determination of NDMA content in - metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb
  • the pharmaceutical dosage form comprising metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb - 72 ppb);
  • the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb - 72 ppb);
  • the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb
  • the pharmaceutical dosage form comprising linagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb
  • the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range 30 ppb to 300 ppb);
  • the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range 30 ppb to 300 ppb) in each case for the purpose of verifying the results obtained by the GC-MS method.
  • the pharmaceutical dosage form comprising metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm);
  • the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof / metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm);
  • the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof / metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm).
  • a GC-MS method for determining the content of NDMA as well as a LC-MS methods for de termining the content of DMA according to the present invention can be used for analysis of any phar maceutical dosage form comprising metformin and in any metformin or pharmaceutically acceptable salt thereof.
  • the GC-MS method according to the invention provides for detection limit of 10 ppb and quantification limit of 30 ppb of NDMA relative to the total weight of metformin in the pharmaceutical dosage form.
  • the LC-MS method according to the invention provides for detection limit of 0.6 ppm and quantification limit of 2.1 ppm of DMA relative to the weight of metformin.
  • a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof and having a content of N-nitroso dimethylamine of not more than 48 ppb, relative to the total weight of metformin in the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to any of clauses 5 to 11, wherein the content of the acid is within the range of from 0.01 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form; preferably 0.01 to 20 wt.-%, relative to the total weight of the pharmaceutical dosage form; more preferably 0.01 to 10 wt.-%, relative to the total weight of the pharmaceutical dosage form.
  • the pharmaceutical dosage form according to any of the preceding clauses wherein the physio logically acceptable salt of metformin is the hydrochloride.
  • the pharmaceutical dosage form according to any of the preceding clauses which contains one or more binders/diluents.
  • the pharmaceutical dosage form according to any of the preceding clauses which contains an additional active pharmaceutical ingredient other than metformin or the physiologically accepta ble salt thereof.
  • step (ix) optionally, film coating the compressed core by applying a liquid coating composition.
  • step (v) is performed as wet granulation by granu lating the first mixture with a granulation fluid, optionally containing one or more excipients, and optionally containing one or more additional active pharmaceutical ingredients.
  • an acid as defined in any of clauses 5 to 13 is (a) among the one or more excipients employed in step (iv);
  • step (b) among the one or more excipients employed in step (vii);
  • the process according to any of clauses 34 to 36, wherein the ground metformin or physiologi cally acceptable salt thereof obtained in step (ii) has a median diameter Dw50, determined by sieve analysis in accordance with Ph. Eur., of not more than 200 pm; preferably not more than 100 pm; more preferably not more than 40 pm.
  • step (iii) is performed in a fluid bed dryer or drying chamber.
  • step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C, more preferably of at least 70°C.
  • a pharmaceutical dosage form obtainable by the process according to any of clauses 34 to 40.
  • a metformin starting material for incorporation into a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof, wherein the content of metformin or the physiologically acceptable salt thereof is at least 99.0 wt.-%, relative to the total weight of the metformin starting material wherein the material has a content of dimethylamine of not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the weight of metformin.
  • a metformin starting material for incorporation into a pharmaceutical dosage form according to clause 42 wherein the metformin or a physiologically acceptable salt thereof is present as a pow der having a median diameter D(50), determined laser diffraction analysis, of not more than 200 pm; preferably not more than 100 pm.
  • step (iii) subjecting the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physiologically acceptable salt thereof.
  • step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.
  • step (iii) is performed in a fluid bed dryer or drying chamber.
  • step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C.
  • median diameter refers to the volume median diameter of the particle size distribution.
  • average particle size refers to the volume average or volume mean diameter of the particle size distribution.
  • the median particle size and average particle size can be determined by laser light scatter ing using e.g. Malvern Mastersizer equipped with »wet « dispersion unit. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The particles to be subjected to the particle size measurement are first suspended in appropriate non polar dispersant such as acetone and then subjected to a size determination in a Malvern Mastersizer instrument. Usually, 100-800 mg of substance is dispersed in 5-10 mL of dispersant.
  • Values D(10), D(50) and D(90) indicate that 10%, 50% and 90% of the particles, respectively, are smaller than the specified values.
  • Ph. Eur. 10.4, 2.9.31 Particle size analysis by laser light diffraction
  • the sample was suspended in a water based solvent to ensure total metformin solubility.
  • Typi cally an amount of sample, corresponding to about 400 mg of metformin was suspended in 8.0 mL of 1M NaOH. After mixing and centrifugation, clear supernatant was extracted with 0.5 mL organic sol vent.
  • the organic solvent for the determination of NDMA in metformin, sitagliptin/metformin and linagliptin/metformin pharmaceutical dosage forms is chloroform.
  • the organic solvent for the determi nation of NDMA in vildagliptin/metformin tablets is dichloromethane.
  • Preparation of mobile Phase A Add 1 mL of formic acid in to 1000 mL of milli-q-water. Filter through 0.45 pm membrane filter and degas it.
  • Preparation of mobile Phase B Add 1 mL of formic acid in to 1000 mL of methanol. Filter through 0.45 pm membrane fdter and degas it.
  • Quantification can be performed by means of a calibration curve that was previously measured with samples of known content of DMA.
  • Metformin hydrochloride is sieved on sieve size 0.6 - 2.0 mm or is ground by the process de scribed below. Metformin hydrochloride or a mixture of metformin hydrochloride and mannitol is dried in a fluid bed dryer or drying chamber for at least 10 minutes, preferably for at least 20 minutes at a temperature of at least 40 °C, preferably at least 50°C.
  • Metformin hydrochloride is ground when passing through a mechanical mill at the prescribed speed [rpm] using the prescribed type of mesh [mm] . Grind ing is performed in stages in a stream of nitrogen. If the product does not meet the particle size require ment after the first stage of grinding, the grinding is repeated at settings within the prescribed limits.
  • the milled metformin has an average and median particle size D(50) in the range of 100 pm to 200 pm. Further, the milled metformin preferably has a particle size distribution of D(10) in the range of 10 to 70 pm, D(50) in the range of 80 pm to 200 pm, and D(90) in the range 150 pm to 400 pm; preferably D(10) from 20 pm to 60 pm, D(50) from 100 pm to 180 pm, and D(90) from 150 pm to 350 pm.
  • the finely milled metformin preferably has an average and median particle size D(50) of less than 100 pm, preferably less than 80 pm. Further, the finely milled metformin preferably has a particle size distribution of D(10) less than 30 pm, D(50) less than 100 pm, and D(90) less than 150 pm; preferably D(10) is less than 20 pm, D(50) less than 80 pm, and D(90) less than 120 pm.
  • Metformin granulation Hydroxypropylcellulose is added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained.
  • the granulation liquid for metfor min granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations.
  • Metformin hydrochloride is de- lumped and sieved on sieve size 0.6 - 2.0 mm.
  • the blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous.
  • the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.
  • Blending compression mixture preparation: Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.
  • Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.
  • Dosage forms were prepared having the following composition: [0141] The pharmaceutical dosage forms were prepared as follows:
  • Metformin granulation Hydroxypropylcellulose and organic acid are added to ethanol, an hydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained.
  • the granulation liquid for metformin granulation and joint granulation is the same, i.e. comprising hydroxypropylcellu lose and ethanol, anhydrous, and can be prepared in a single step for both granulations.
  • Metformin hy drochloride is delumped and sieved on sieve size 0.6 - 2.0 mm.
  • the blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous.
  • the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.
  • Blending compression mixture preparation: Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.
  • Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, fdm coated tablets are kept rotating to dry and cooled until reaching the temperature of fdm coated tablets below 30°C.
  • the pharmaceutical dosage forms were prepared as follows: [0151] a) Metformin granulation: Hydroxypropylcellulose is added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained.
  • the granulation liquid for metfor min granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations.
  • Metformin hydrochloride is de- lumped and sieved on sieve size 0.6 - 2.0 mm.
  • the blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous.
  • the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.
  • Blending compression mixture preparation: Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate.
  • Organic acid is sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof.
  • the lubricants, organic acid and joint granulate are mixed for 30 - 70 revolutions.
  • Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.
  • Metformin granulation Hydroxypropylcellulose and are added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained.
  • the granulation liquid for metformin granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations.
  • Metformin hydrochloride is delumped and sieved on sieve size 0.6 - 2.0 mm.
  • the blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous.
  • the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.
  • Blending compression mixture preparation: Sodium stearyl fiimarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.
  • Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.
  • Metformin drying Metformin hydrochloride is de lumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is dried in fluid bed dryer at product temper ature of 70°C for one hour.
  • Metformin granulation Hydroxypropylcellulose is added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained.
  • the granulation liquid for metfor min granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations.
  • Dry blend of metformin hydro chloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous. After completing granulation, the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.
  • Blending compression mixture preparation: Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.
  • f) Tableting Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.
  • g) Film-coating Coating mixture and colorant ferric oxide yellow (E 172) are homogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:
  • Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.
  • Packaging procedure Packaging process is being carried out under the same conditions as manufacturing process.
  • DMA content of the metformin hydrochloride that was employed as staring material was determined by the LC-MS method according to the invention as described above.
  • DMA content after treatment was also determined.
  • NDMA content was determined by the GC-MS method according to the invention as described above. NMDA content of the manufactured pharmaceutical dosage forms was measured before storage under stressed conditions and after 14 days of storage, in some cases additionally after 1 month of stor age, in each case under stressed storage conditions (50°C/75% rh).
  • the pharmaceutical dosage forms according to the invention have a significantly reduced content of NDMA.
  • This can be achieved by (i) reducing the DMA content in the starting material of the active pharmaceutical ingredient, i.e. metformin or physio logically acceptable salt thereof, preferably by drying and/or milling; and (ii) adding an acid that appears to stabilize metformin or physiologically acceptable salt thereof thereby suppressing DMA release.
  • the results show that the pharmaceutical dosage forms which comprise milled metformin and a pharmaceu tically acceptable acid are more stable on storage at stress conditions and exhibit lower increase of the content of NDMA. This is further improved by incorporation of the active ingredient comprising lower contents of DMA.
  • Metformin hydrochloride was treated under various conditions (with and without milling, dry ing at 50°C and 70°C) and the influence on DMA content over time was investigated. DMA content was determined by the LC-MS method according to the invention as described above.
  • the data in the above table shows the decrease in the DMA content (presumably of the volatile part of DMA) in metformin, depending on the drying time.
  • the decrease in content is more pronounced (relative to the initial content) in metformin with a smaller average particle size (milled), indicating trapping of the volatile part of DMA in the crystal lattice of metformin.

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Abstract

L'invention concerne une matière de départ à base de metformine destinée à être incorporée dans une forme pharmaceutique comprenant de la metformine ou un sel physiologiquement acceptable de celle-ci, la teneur en metformine étant d'au moins 99,0 % en poids par rapport au poids total de matière de départ à base de metformine, la matière ayant une teneur en diméthylamine ne dépassant pas 180 ppm par rapport au poids de metformine, et la metformine étant présente sous forme d'une poudre ayant un diamètre D(50) médian en volume inférieur ou égal à 200 µm, déterminé par analyse de diffraction laser. L'invention concerne également un procédé de préparation d'une matière de départ à base de metformine, le procédé comprenant les étapes consistant à : (i) fournir de la metformine ou un sel physiologiquement acceptable de celle-ci ; (ii) broyer la metformine ou un sel physiologiquement acceptable de celle-ci, ce qui permet d'obtenir de la metformine ou un sel physiologiquement acceptable de celle-ci sous forme broyée ; et (iii) soumettre la metformine ou un sel physiologiquement acceptable de celle-ci, ou la metformine ou un sel physiologiquement acceptable de celle-ci sous forme broyée, à une température élevée et/ou à une pression réduite, ce qui permet d'obtenir de la metformine ou un sel physiologiquement acceptable de celle-ci sous forme séchée. L'invention concerne en outre un procédé de préparation d'une forme pharmaceutique comprenant de la metformine ou un sel physiologiquement acceptable de celle-ci et ayant une teneur en N-nitrosodiméthylamine ne dépassant pas 48 ppb par rapport au poids total de metformine dans la forme pharmaceutique, ledit procédé comprenant le procédé mentionné ci-dessus.
PCT/EP2021/070703 2020-07-31 2021-07-23 Formulation pharmaceutique de metformine ayant une faible teneur en diméthylamine Ceased WO2022023213A1 (fr)

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EP4454703A3 (fr) * 2020-10-16 2024-12-25 Zentiva K.S. Compositions pharmaceutiques à faibles quantités d'impuretés nitrosamine et leurs procédés de production
WO2025058361A1 (fr) * 2023-09-11 2025-03-20 동광제약 주식회사 Procédé de réduction d'impureté de diméthylamine présentes à l'intérieur du chlorhydrate de metformine

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