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WO2011051974A1 - Metformine et acides aminés alpha - Google Patents

Metformine et acides aminés alpha Download PDF

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Publication number
WO2011051974A1
WO2011051974A1 PCT/IN2010/000704 IN2010000704W WO2011051974A1 WO 2011051974 A1 WO2011051974 A1 WO 2011051974A1 IN 2010000704 W IN2010000704 W IN 2010000704W WO 2011051974 A1 WO2011051974 A1 WO 2011051974A1
Authority
WO
WIPO (PCT)
Prior art keywords
metformin
pharmaceutical
amino acid
crystals
crystal composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2010/000704
Other languages
English (en)
Inventor
Jaggavarapu Satyanarayana Reddy
Rambabu Dandela
Ganesh Saraswatula Viswanadha
Ravikumar Nagalapalli
Anand Kamalakaram Solomon
Iqbal Javed
Anil Kumar Kruthiventi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nutracryst Therapeutics Pvt Ltd
Original Assignee
Nutracryst Therapeutics Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nutracryst Therapeutics Pvt Ltd filed Critical Nutracryst Therapeutics Pvt Ltd
Publication of WO2011051974A1 publication Critical patent/WO2011051974A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • This invention relates to the field of pharmaceutical co crystals. More particularly, the present invention relates to synergistic pharmaceutical co crystals comprising Metformin in combination with amino acids.
  • the pharmaceutical co-crystals of Metformin-amino acid have unique physical properties and biological activity which differ from the active agent in pure form.
  • the invention further relates to process for preparation of the same and also relates to pharmaceutical compositions comprising these synergistic co-crystals.
  • compositions are defined as hydrogen bonded complexes between an active pharmaceutical ingredient (API) and a coformer (CCF, benign partner molecule), usually having a fixed API: CCF stoichiometry.
  • API active pharmaceutical ingredient
  • CCF benign partner molecule
  • co-crystals were known as early as 19 th century, the pharmaceutical industry has recognized the potential for their applications only recently.
  • Pharmaceutical co- crystals are crystalline molecular complexes containing therapeutic molecules. These co crystals represent emerging class of pharmaceutical materials offering the prospects of optimized physical properties as discussed.
  • co-crystals have utility in imparting desirable physical properties and stability, which are otherwise not achievable for the pure active agent or in combination as a simple formulation using the excipients incorporated with the active agent.
  • Pharmaceutical co-crystals are crystalline molecular complexes containing therapeutic molecules. These co-crystals represent emerging class of pharmaceutical materials offering the prospects of optimized physical as well as therapeutic properties.
  • Metformin is an oral anti-diabetic drug from the biguanide class. It is the first-line drug for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function. Evidence suggests it may be the best choice for people with heart failure. It is also used in the treatment of polycystic ovary syndrome. Though, Metformin causes few adverse effects, like gastrointestinal upset, however, unlike many other anti-diabetic drugs, do not cause hypoglycemia if used alone. It also helps to reduce LDL cholesterol and triglyceride levels, and may aid weight loss.
  • Metformin is most widely used first line drug for diabetes type II. Its mechanism of action involves raising peripheral glucose uptake by increasing both the binding capacity of insulin to its receptor and the translocation and synthesis of glucose transporters.
  • Metformin has an oral bioavailability of 50-60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (C max ) are reached within one to three hours of taking immediate-release Metformin and four to eight hours with extended-release formulations. The plasma protein binding of Metformin is negligible, as reflected by its very high apparent volume of distribution (300-1000 L after a single dose).
  • Protein binding can influence the drug's biological half-life in the body.
  • the bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium.
  • Metformin is available in the market as immediate release and sustained release tablet form.
  • prior art failed to provide alternate synergistic bioavailable dosage forms of Metformin to enhance the residence time of Metformin in the blood.
  • a-amino acids are naturally occurring biomolecules. Apart from being essential building blocks for the proteins, alpha-am inoacids have a wide range of biological action.
  • L-Isoleucine - is needed in regulating sugar and the energy levels, as well as in the formation of hemoglobin. This amino acids is transformed and converted into muscle tissue. Lack of this AA produces a symptom similar to hypoglycemia or low blood sugar.
  • L-Leucine - an important amino acid, which is found in animal and vegetable proteins. It is important for controlling the blood sugar level. L-Lysine - an important for the construction of proteins principally in muscles and bones. Helps the assimilation of calcium, to obtain greater mental concentration and helps to lessen the effects of colds, flu and the herpes virus. It helps in the production of hormones, antibodies, enzymes and also in the formation of collagen. The deficiency of this amino acid produces: fatigue, irritability, anemia, and hair loss.
  • L-Methionine - helps to remove poison wastes from the liver and take part in the formation of the liver and kidney tissues. Help the digestive system, weak muscles, fragile hair, and is beneficial for osteoporosis.
  • L-Phenylalanine helps against depression, obesity, and loss of memory. It is an important element in the production of collagen, the principal fibrous protein in the body. Due to its action in the central nervous system, these amino acids decrease the pain associated with migraines, menstruation, and arthritis. L-Phenylalanine should not be taken by pregnant women or those who suffer from high blood pressure.
  • L-Tryptophan - helps control hyperactivity in children, alleviate stress, is good for the heart. It helps in weight control and allows the growth of the hormones necessary for the production of Vitamin B6 and Niacin.
  • the brain utilizes this amino acid to produce Seratonina and Melatonina, neurotransmitters necessary for transferring nervous impulses from one cell to another. Lack of them (viz. Serotonine and Melatonine) produces depression, loss of sleep and other mental disorders.
  • L-Threonine - found in the heart, central nervous system and muscles. It is beneficial in the formation of collagen and elastin. Helps the liver and maintain the body's proteins in balance.
  • L- Valine - has a stimulating effect. It maintains the metabolism of muscles, repairs tissues and balances nitrogen. Valine should be combined with Leucine and isoleucine.
  • L-Alanine - acts as a producer of energy and it regulates blood sugar. Also, intervenes in the metabolism of glucose.
  • L-Asparagine - is important in the metabolic process of the nervous system.
  • L-Aspartic Acid - is essential for the transformation of carbohydrates into muscular energy.
  • L-Citruline - immune system stimulator helps in the production of body energy and helps to detoxify the liver from ammonia substance.
  • L-Cysteine - stimulates the growth of hair and protects against the damages that can be caused by alcohol and cigarettes.
  • L-Glutamine - helps the memory, concentration, and the correct functioning of mental activity.
  • L-Glutamic Acid - helps in the production of energy and brain function.
  • L-Glycine - slow the muscle degeneration by supplying addional creatine.
  • Glucose and creatine are 2 essential substances in the production of energy and require glycine in their synthesis process.
  • L-Histidine important in the production of red and white blood cells, and is vital for the formation of body tissues.
  • L-Proline - is important ingredient in the formation of tissues.
  • L-Serine - aid the memory, the nervous system function, and is very important in the production of cell energy.
  • L-Tyrosine - helps in the treatment of insomnia, anxiety and depression, as well as allergies and is very important in the function of the thyroid and hypophysis glands. Deficiency of this amino acid is associated to hyperthyroidism (can cause fatigue).
  • L-Carnitine - helps control weight and body fat, as well as reduce the risk of heart problems. Lysine and vitamin ⁇ and B6 along with iron are needed for the body to produce this amino acid.
  • GAB A (Gamma- Am inobutyric Acid) - helps stop anxiety and hyperactivity.
  • Amino acids are critical to life, and have a variety of roles in metabolism. One particularly important function is as the building blocks of proteins which are linear chains of amino acids. Amino acids are also important in many other biological molecules, such as forming parts of coenzymes, or as precursors for the biosynthesis of molecules such as heme. Due to this central role in biochemistry, amino acids are very important in nutrition.
  • a-amino acids are useful in regulating sugar and energy levels, moreover, these amino acids being lipophilic helps Metformin in binding with blood plasma protein thereby increasing the plasma protein binding effect of the drug which in turn helps slow release of the drug from the co-crystals in unbound form yet maintaining the equilibrium of the drug levels in the body.
  • the objective of the present invention is to provide synergistic pharmaceutical co-crystals comprising Metformin composed of alpha-amino acids to provide effective treatment of polycystic ovary syndrome, metabolic syndrome, hypoglycemia, hypertension or diabetes Type II with reduced dosage of the active.
  • the present invention discloses a novel synergistic pharmaceutical co-crystal composed of Metformin with at least one alpha amino acid(s).
  • the inventive co-crystal of Metformin can be used in Metformin sustained release dosage forms.
  • Metformin' as described herein also encompasses Metformin salts including Metformin hydrochloride.
  • the invention provides novel synergistic Metformin co-crystals which comprise Metformin and at least one alpha amino acid(s).
  • Alpha amino acids are selected from Leucine, isoleucine, lysine, methionine, phenyl alanine, threonine, tryptophan, valine, alanine, asparagines, aspartic acid, cystenine, glutamic acid, glutamine, glycine, proline, serine, tyrosine, arginine, and histidine.
  • the Bioavailability / blood plasma binding of Metformin is poor, hence these co-crystals (specially the ones with lipophilic amino acids) will enhance the blood plasma binding ability of Metformin, thereby enhancing the 'time of residence' of Metformin in the blood. This would naturally translate to improving the efficacy, and hence lowering the dose of Metformin.
  • the pharmaceutical co-crystal composed of Metformin with alpha amino acids is useful to treat polycystic ovary syndrome, metabolic syndrome, hypoglycemia, hypertension or diabetes Type II.
  • the invention provides the metformin-amino acid co-crystals, wherein said method comprises neat grinding of Metformin free base and amino acid in 1:1 ratio.
  • the invention provides novel pharmaceutical composition comprising Metformin-amino acid co-crystals of the current invention in association with one or more pharmaceutical carriers.
  • the invention also provides methods for the treatment of the disorder discussed above.
  • Metformin co-crystals and pharmaceutical compositions containing them may, according to the invention, be administered using any amount, any form of pharmaceutical composition and any route of administration effective for the treatment.
  • the pharmaceutical compositions of this invention can be administered by any means that delivers the active pharmaceutical ingredient (s) to the site of the body whereby it can exert a therapeutic effect on the patient.
  • Fig 1 shows the PXRD profile of Metformin
  • Fig 2 shows the PXRD profile of L- Leucine
  • Fig 3 shows the PXRD profile of co-crystal of Metformin-L- Leucine
  • Fig 4 shows the PXRD profile of L-Alanine
  • Fig 5 shows PXRD profile of co-crystal of Metformin and L-alanine
  • Fig 6 shows IR spectra of Metformin
  • Fig 7 depicts IR spectra of L-Leucine
  • Fig 8 depicts IR spectra of co-crystal of Metformin-L-Leucine.
  • ig 9 depicts DSC of Metformin
  • ig 10 depicts DSC of L-Leucine
  • ig 1 1 depicts DSC of co-crystal of Metformin- L-Leucine
  • Fig 12 depicts TGA of Metformin
  • ig 13 depicts TGA of L-Leucine
  • ig 14 depicts TGA of co-crystal of Metformin-L-Leucine Description of the invention:
  • the present invention discloses novel synergistic pharmaceutical co-crystals composed of Metformin with at least one alpha amino acid(s).
  • the inventive co-crystal of Metformin can be used in Metformin sustained release dosage forms.
  • the invention provides novel synergistic Metformin co-crystals which comprise metform and alpha amino acid.
  • Alpha amino acids are selected from leucine, isoLeucine, lysine, methionine, phenyl alanine, threonine, tryptophan, valine, alanine, asparagines, aspartic acid, cystenine, glutamic acid; glutamine, glycine, proline, serine, tyrosine, arginine, and histidine.
  • the Bioavailability / blood plasma binding of Metformin is poor, hence these co-crystals (specially the ones with lipophilic amino acids) will enhance the blood plasma binding ability of Metformin, thereby enhancing the 'time of residence' of Metformin in the blood. This would naturally translate to improving the efficacy, and hence lowering the dose of Metformin.
  • the pharmaceutical co-crystal composed of Metformin with alpha amino acids is useful to treat polycystic ovary syndrome, metabolic syndrome, hypoglycemia, hypertension or diabetes Type II.
  • the invention provides the metformin-amino acid co-crystals, wherein said method comprises neat grinding of Metformin free base and amino acid in 1 : 1 ratio and isolating the co-crystals.
  • the process involves solvent drop grinding method. Generally co- crystals appear in 2-3 days. The formation of these co-crystal or salt was confirmed by powder X-ray powder diffractometry, IR spectrometry, DSC and TGA.
  • the co-crystal melts in-between the melting points of co-crystal formers (more often) or below their melting points (less often).
  • Metformin co-crystal with L- Leucine (1 : 1) start to decompose at 167 °C which is higher than the melting point of Metformin free base and lower than the melting point of L-Leucine.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of Metformin-amino acid co-crystals of the current invention in association with one or more pharmaceutical carriers.
  • the co-crystals of the invention have the same pharmaceutical activity as its API.
  • the pharmaceutical composition of the invention may be any pharmaceutical form which maintains the crystalline form of a co-crystal of the invention.
  • the pharmaceutical composition may be a solid form, a liquid suspension or an injectable composition.
  • the present invention provides a method of reducing symptoms associated with polycystic ovary syndrome, metabolic syndrome, hypoglycemia, hypertension or diabetes Type II, which method comprises administering 'an effective amount' of the 'Metformin and alpha amino acid co-crystals' to the subject suffering from polycystic ovary syndrome, metabolic syndrome, hypoglycemia, hypertension or diabetes Type II.
  • the subject mentioned herein is human.
  • Metformin co-crystals and pharmaceutical compositions containing them may, according to the invention, be administered using any amount, any form of pharmaceutical composition and any route of administration effective for the treatment.
  • the pharmaceutical compositions of this invention can be administered by any means that delivers the active pharmaceutical ingredient (s) to the site of the body whereby it can exert a therapeutic effect on the patient.
  • the invention further discloses use of the 'composition of the invention comprising Metformin and alpha amino acid co-crystals' in preparing the medicament intended to reduce symptoms associated with polycystic ovary syndrome, metabolic syndrome, hypoglycemia, hypertension or diabetes Type II.
  • Metformin free base (synthesized from Metformin hydrochloride in house) and L-Leucine (Aldrich - Sigma) in 1 : 1 ratio was neat grinded for 5 min to yield the new co-crystal of Metformin+ L-Leucine.
  • Metformin free base (synthesized from Metformin hydrochloride in house) and L-alanine (Aldrich - Sigma) in 1: 1 ratio was neat grinded for 5 min to yield the new co-crystal of Metformin+ L-alanine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition synergique de co-cristaux pharmaceutiques de metformine et d'au moins un acide aminé alpha.
PCT/IN2010/000704 2009-10-29 2010-10-28 Metformine et acides aminés alpha Ceased WO2011051974A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2237/DEL/2009 2009-10-29
IN2237DE2009 2009-10-29

Publications (1)

Publication Number Publication Date
WO2011051974A1 true WO2011051974A1 (fr) 2011-05-05

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103889411A (zh) * 2011-07-15 2014-06-25 纽斯尔特科学公司 用于调节代谢途径的组合物和方法
WO2014124141A1 (fr) * 2013-02-07 2014-08-14 Mylari Banavara L Dérivés de metformine pour le traitement du diabète
US9198454B2 (en) 2012-03-08 2015-12-01 Nusirt Sciences, Inc. Compositions, methods, and kits for regulating energy metabolism
US9707213B2 (en) 2013-03-15 2017-07-18 Nusirt Sciences, Inc. Compositions, methods and kits for reducing lipid levels
US9724319B2 (en) 2014-02-27 2017-08-08 Nusirt Sciences, Inc. Compositions and methods for the reduction or prevention of hepatic steatosis
US9943517B2 (en) 2012-11-13 2018-04-17 Nusirt Sciences, Inc. Compositions and methods for increasing energy metabolism
WO2018060962A3 (fr) * 2016-09-30 2018-05-24 Laboratorios Silanes S.A. De C.V. Composés d'acides aminés de metformine et leurs procédés d'utilisation
EP3369419A4 (fr) * 2015-10-30 2018-10-31 Yasumasa Kato Composition pour le traitement du diabète
CN113354596A (zh) * 2021-06-01 2021-09-07 天津大学 依帕司他-二甲双胍盐丙酮溶剂化物及制备方法和应用
US20210315963A1 (en) * 2018-08-10 2021-10-14 Diapin Therapeutics, Llc Tri-peptides and treatment of metabolic, cardiovascular and inflammatory disorders
US11185516B2 (en) 2016-09-30 2021-11-30 Laboratorios Silanes S.A. De C.V. Metformin glycinate, pharmaceutical compositions comprising the same, and methods of using the same
CN114555043A (zh) * 2019-08-21 2022-05-27 株式会社Lg生活健康 包含共晶混合物的化妆料组合物
US11701336B2 (en) 2015-10-30 2023-07-18 Yasumasa Kato Method of determining composition effective for treating diabetes

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Publication number Priority date Publication date Assignee Title
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WO2006102752A1 (fr) * 2005-03-30 2006-10-05 Generex Pharmaceuticals Inc. Compositions pour l'administration de metformine par voie transmuqueuse orale
US20070265349A1 (en) * 2000-12-29 2007-11-15 Dospharma Medicinal association of a biguanine and a carrier, for example metformin and arginine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219480A1 (en) * 1999-12-20 2003-11-27 Fassihi A. Reza Amino acid modulated extended release dosage form
US20070265349A1 (en) * 2000-12-29 2007-11-15 Dospharma Medicinal association of a biguanine and a carrier, for example metformin and arginine
WO2006102752A1 (fr) * 2005-03-30 2006-10-05 Generex Pharmaceuticals Inc. Compositions pour l'administration de metformine par voie transmuqueuse orale

Non-Patent Citations (1)

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Title
MARFELLA R. ET AL: "Metformin improves hemodynamic and rheological responses to L-arginine in NIDDM patients", DIABETES CARE, vol. 19, no. 9, September 1996 (1996-09-01), pages 934 - 939, XP001036613 *

Cited By (33)

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US10076507B1 (en) 2011-07-15 2018-09-18 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
CN103889411A (zh) * 2011-07-15 2014-06-25 纽斯尔特科学公司 用于调节代谢途径的组合物和方法
JP2014520864A (ja) * 2011-07-15 2014-08-25 ニューサート サイエンシーズ， インコーポレイテッド 代謝経路を変調させるための組成物および方法
EP2731599A4 (fr) * 2011-07-15 2015-04-08 Nusirt Sciences Inc Compositions et procédés de modulation de voies métaboliques
US9072692B2 (en) 2011-07-15 2015-07-07 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
CN103889411B (zh) * 2011-07-15 2018-03-16 纽斯尔特科学公司 用于调节代谢途径的组合物和方法
US9198883B1 (en) 2011-07-15 2015-12-01 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
US9351967B2 (en) 2011-07-15 2016-05-31 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
US9855235B2 (en) 2011-07-15 2018-01-02 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
US9682053B2 (en) 2011-07-15 2017-06-20 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
AU2012284267B2 (en) * 2011-07-15 2017-06-29 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
US10383837B2 (en) 2011-07-15 2019-08-20 Nusirt Sciences, Inc. Compositions and methods for modulating metabolic pathways
US9408410B2 (en) 2012-03-08 2016-08-09 Nusirt Sciences, Inc. Compositions, methods, and kits for regulating energy metabolism
US9713609B2 (en) 2012-03-08 2017-07-25 Nusirt Sciences, Inc. Compositions, methods, and kits for regulating energy metabolism
US9901573B2 (en) 2012-03-08 2018-02-27 Nusirt Sciences, Inc. Compositions, methods, and kits for regulating energy metabolism
US9198454B2 (en) 2012-03-08 2015-12-01 Nusirt Sciences, Inc. Compositions, methods, and kits for regulating energy metabolism
US10646489B2 (en) 2012-11-13 2020-05-12 Nusirt Sciences, Inc. Compositions and methods for increasing energy metabolism
US9943517B2 (en) 2012-11-13 2018-04-17 Nusirt Sciences, Inc. Compositions and methods for increasing energy metabolism
WO2014124141A1 (fr) * 2013-02-07 2014-08-14 Mylari Banavara L Dérivés de metformine pour le traitement du diabète
US9895357B2 (en) 2013-03-15 2018-02-20 Nusirt Sciences, Inc. Compositions, methods and kits for reducing lipid levels
US9707213B2 (en) 2013-03-15 2017-07-18 Nusirt Sciences, Inc. Compositions, methods and kits for reducing lipid levels
US9872844B2 (en) 2014-02-27 2018-01-23 Nusirt Sciences, Inc. Compositions and methods for the reduction or prevention of hepatic steatosis
US9724319B2 (en) 2014-02-27 2017-08-08 Nusirt Sciences, Inc. Compositions and methods for the reduction or prevention of hepatic steatosis
US11701336B2 (en) 2015-10-30 2023-07-18 Yasumasa Kato Method of determining composition effective for treating diabetes
EP3369419A4 (fr) * 2015-10-30 2018-10-31 Yasumasa Kato Composition pour le traitement du diabète
US11510886B2 (en) 2016-09-30 2022-11-29 Laboratorios Silanes, S.A. De C.V. Metformin amino acid compounds and methods of using the same
US11185516B2 (en) 2016-09-30 2021-11-30 Laboratorios Silanes S.A. De C.V. Metformin glycinate, pharmaceutical compositions comprising the same, and methods of using the same
WO2018060962A3 (fr) * 2016-09-30 2018-05-24 Laboratorios Silanes S.A. De C.V. Composés d'acides aminés de metformine et leurs procédés d'utilisation
US11951081B2 (en) 2016-09-30 2024-04-09 Laboratorios Silanes S.A. De C.V. Metformin glycinate, pharmaceutical compositions comprising the same, and methods of using the same
US20210315963A1 (en) * 2018-08-10 2021-10-14 Diapin Therapeutics, Llc Tri-peptides and treatment of metabolic, cardiovascular and inflammatory disorders
CN114555043A (zh) * 2019-08-21 2022-05-27 株式会社Lg生活健康 包含共晶混合物的化妆料组合物
CN114555043B (zh) * 2019-08-21 2024-04-12 株式会社Lg生活健康 包含共晶混合物的化妆料组合物
CN113354596A (zh) * 2021-06-01 2021-09-07 天津大学 依帕司他-二甲双胍盐丙酮溶剂化物及制备方法和应用

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