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WO2022208216A1 - An oral liquid formulation of metformin, teneligliptin, vitamin b12, atorvastatin and levothyroxine for diabetes - Google Patents

An oral liquid formulation of metformin, teneligliptin, vitamin b12, atorvastatin and levothyroxine for diabetes Download PDF

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Publication number
WO2022208216A1
WO2022208216A1 PCT/IB2022/052354 IB2022052354W WO2022208216A1 WO 2022208216 A1 WO2022208216 A1 WO 2022208216A1 IB 2022052354 W IB2022052354 W IB 2022052354W WO 2022208216 A1 WO2022208216 A1 WO 2022208216A1
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Prior art keywords
formulation
metformin
concentration
range
diabetes
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PCT/IB2022/052354
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French (fr)
Inventor
Boggarapu Prakash Rao
Kalavathy DODDABANDARA JAVAREGOWDA
Rashmi Mathews MATHEWS
Buvanagiri SUDHA
Gutta Prabhakar RAO
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Boggarapu, Shravya
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Priority to AU2022249968A priority Critical patent/AU2022249968A1/en
Publication of WO2022208216A1 publication Critical patent/WO2022208216A1/en

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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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]
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a formulation comprising metformin hydrochloride for the treatment of type 2 diabetes. More particularly, the invention discloses the formulation, which is a combination of metformin hydrochloride, teneligliptin, vitamin B12, levothyroxine sodium and atorvastatin in a liquid sustained dosage form for treatment of type 2 diabetes in patients. The formulation is suitable for oral administration even in patients with swallowing difficulty. The invention also discloses a composition of an aqueous and taste masking conventional and sustained liquid, semi-liquid, and solid dosage forms for water-soluble and water-insoluble bitter drugs. Background of the invention
  • Diabetes mellitus commonly known as diabetes is a metabolic disease that causes high blood glucose.
  • the hormone insulin transfers glucose from the blood into the cells to be stored or used for energy.
  • the body either does not produce enough insulin from pancreas or can’t effectively use the insulin it does make causing the higher blood glucose level.
  • Type 1 diabetes which is an autoimmune disease.
  • the immune system attacks and destroys the cells in the pancreas, where insulin is synthesized. About 10% of the human population with diabetes has this type.
  • type 2 diabetes which occurs when the body becomes resistant to insulin, and glucose builds up in blood. Prediabetes occurs when blood glucose is higher than normal, but it’s not high enough for a diagnosis of type 2 diabetes.
  • gestational diabetes is high blood glucose during pregnancy and shall be normalized post-delivery. Insulin-blocking hormones produced by the placenta cause this type of diabetes.
  • the risk factors for prediabetes and type 2 diabetes are similar. They include being overweight, a family history of diabetes, having a high-density lipoprotein (HDL) cholesterol level lower than 40 mg/dL or 50 mg/dL, a history of high blood pressure, having gestational diabetes or giving birth to a child with a birth weight of more than 9 pounds, a history of polycystic ovary syndrome (PCOS), being more than 45 years of age, having a sedentary lifestyle etc.
  • HDL high-density lipoprotein
  • PCOS polycystic ovary syndrome
  • Type 2 diabetes mellitus is a chronic metabolic disorder in which prevalence has been increasing steadily all over the world. As a result of this trend, it is fast becoming an epidemic in some countries of the world with the number of people affected expected to double in the next decade due to increase in ageing population, thereby adding to the already existing burden for healthcare providers, especially in poorly developed countries. It is estimated that 366 million people had diabetes mellitus in 2011, by 2030 this would have risen to 552 million. The number of people with type 2 diabetes mellitus is increasing in every country with 80% of people with diabetes mellitus living in low- and middle-income countries.
  • GLP-1 Glucagon-like peptide 1
  • DPP-IV Dipeptidyl peptidase-IV inhibitor
  • the adipose tissue plays a crucial role in the pathogenesis of type 2 diabetes mellitus. This constitutes the framework for the analysis of the interplay between insulin resistance and beta-cell dysfunction in type 2 diabetes as well as between obesogenic environment and diabetes risk in the next decade.
  • Biguanides of which metformin HC1 is the most commonly used in overweight and obese patients, suppresses hepatic glucose production, increases insulin sensitivity, enhances glucose uptake by phosphorylating GLUT-enhancer factor, increases fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal tract.
  • Taste is a crucial factor that determines the palatability of oral dosage form and patient compliance. It also gives a unique identity to a product and thereby provides a competitive advantage to a company, especially in the case of over-the-counter products.
  • Taste-masking techniques are applied to mask or overcome the bitter or unpleasant taste of active pharmaceutical ingredients or drugs to achieve patient acceptability and compliance. Oral administration of bitter or unpleasant tasting drugs is often the biggest barrier for patient groups, such as pediatrics and geriatrics. Unless the active ingredient is tasteless or does not have any unpleasant taste, taste-masking plays a key role in the success of a final solid oral dosage form.
  • the efficiency of taste-masking is often a key determinant for the success of specialized dosage forms such as orally disintegrating tablets and films, and chewable tablets.
  • the mechanisms of taste-masking techniques often rely on two major approaches: the first is to add sweeteners, flavors, and effervescent agents to mask the unpleasant taste, and the second is to avoid the contact of bitter or unpleasant drugs with taste buds.
  • Polymers constitute a group of materials having a wide-ranging impact on modern pharmaceutical technology.
  • Polymeric components provide the foundation for the advancement of novel drug delivery platforms, inter alia orodispersible films.
  • Orodispersible films are thin, polymeric scraps intended to dissolve quickly when put on the tongue, allowing them to be easily swallowed without the necessity of drinking water, thus eliminating the risk of choking, which is of great importance in the case of pediatric and geriatric patients.
  • Polymers are essential excipients in designing orodispersible films, as they constitute the backbone of these drug dosage forms. The type of polymer is of significant importance in obtaining the formulation of the desired quality.
  • a variety of natural and synthetic polymers currently utilized in manufacturing of orodispersible films might be used alone or in a blend.
  • the Patent Application No. W02018033808A1 entitled “ Improved composition of teneligliptin and metformin HCl and method for preparing same ” relates to an improved pharmaceutical composition in the form of a coated oral tablet, with teneligliptin or the pharmaceutically acceptable salts thereof and metformin HCl or the pharmaceutically acceptable salts thereof, for the treatment of type 2 diabetes mellitus.
  • the pharmaceutical composition is obtained by means of wet granulation, using metformin HCl ground to a fine powder and a low load of excipients consisting of a binder, in this case povidone, and magnesium stearate as a lubricant during compression.
  • the use of ground metformin HCl considerably improves the compressibility of same, allowing operative conditions to be optimized.
  • the improved pharmaceutical composition comprising the combination of teneligliptin and metformin HCl show no differences in in vitro release (solution), and, moreover, improved the compressibility of the powder and the friability of the tablets.
  • the features mentioned distinguish this improved composition from other compositions containing the same active ingredients and using more excipients.
  • IL158506A entitled “ Oral pharmaceutical form for a single daily intake combining a metformin HCl and at least one other antidiabetic active principle” discloses antidiabetic (type II diabetes) oral galenic form comprising an ' active principle A chosen from biguanides, metformin HCl being particularly preferred, A being combined with at least one other antihyperglycemic active principle B.
  • composition containing metformin, useful as antidiabetic, is formulated as water-soluble granules for administration, after dissolution, through a gastric tube discloses a composition containing metformin HCl as active agent and auxiliaries, is formulated as water-soluble granulate.
  • An independent claim is also included for device for administering a (I) solution (as a drink), comprising a gastric tube that can be linked, through a connecting piece, to a container holding a predetermined dose of the (I) solution.
  • the Patent Application No. KR20060006469A entitled “ Oral antidiabetic composition comprising metformin HCl and glimepiride and the preparation method thereof relates to a pharmaceutical composition for treating oral diabetes comprising metformin HCl and glimepiride together with a pharmaceutically acceptable carrier.
  • the present invention forms a wet granule with a disintegrant in metformin, glimepiride, and wet granules, and after the formation of granules by mixing another disintegrant, pharmaceutical disintegrators are included in both wet granulation and post granulation mixing.
  • the Patent Application No. US7767231B2 entitled “ Taste-masking pharmaceutical compositions discloses a pharmaceutical composition for oral administration suitable for the preparation of a ready-to-use suspension comprising coated particles comprising an active substance having an unpleasant and/or bitter taste, such as clarithromycin, and a suspension base comprising an osmotically active substance capable of providing a high osmolality to the admixture of the suspension base with an aqueous suspending medium in the ready-to-use suspension.
  • the said ready-to-use suspension maintains its palatability over a prolonged period by those defined osmotic conditions.
  • the existing formulations may not be effective in all patients due to drug resistance and due to the mode of administration. Hence, there is a need for a formulation with a combination to enhance the antidiabetic activity. Further the existing metformin HC1 compositions are solid dosage forms but does not include effective mode of administration with sustained release for improved efficacy and pharmacokinetic profile.
  • the present invention provides a formulation for treatment of type 2 diabetes.
  • the formulation which is a combination of metformin hydrochloride, teneligliptin, vitamin B12, levothyroxine sodium and atorvastatin in suitable for liquid sustained dosage form.
  • the formulation of the present invention is a combination therapy comprising metformin HC1 at a concentration in the range between 200 mg to 1000 mg, teneligliptin at a concentration in the range between 10 mg to 40 mg, vitamin B12 at a concentration in the range between 0.0024 mg to 0.024 mg, levothyroxine sodium at a concentration in the range between 0.005 mg to 0.050 mg, atorvastatin or pravastatin at a concentration in the range between 5 mg to 10 mg, Poloxamer 407, 331 or 188 at a concentration in the range between 450 mg to 1500 mg, sorbitol at a concentration in the range between 100 mg to 300 mg, sodium benzoate and water.
  • the presence of suitable excipients in the formulation as combination enhances the activity of metformin hydrochloride by exhibiting the synergistic effect.
  • the formulation is unique as it’s useful as liquid dosage form for single dose.
  • the presence of vitamin B12 in the formulation reduces the risk of onset of diabetic neuropathy generally associated with use of metformin HC1.
  • vitamin B12 and levothyroxine sodium in the formulation enhances the efficacy of metformin HC1.
  • the presence of statin in the formulation reduces the risk of insulin resistance by reducing triglycerides level and reduces the blood pressure.
  • metformin HC1 with suitable other ingredients exhibited synergistic activity in anti-diabetic activity.
  • metformin HC1 The dissolution study and the in vitro drug release of metformin HC1 is analyzed up to 12 hours and metformin hydrochloride exhibited release of 93.263 % in 12 hours and interprets good dissolution profile.
  • the formulation is compared with standard metformin in inducing the blood glucose levels in rat model of diabetes.
  • the formulation at a single dosage of 100 mg/kg is effective than standard metformin reducing the blood glucose levels in rat model of diabetes.
  • the present invention also discloses an approach for taste masking the bitter drugs including metformin.
  • the formulation comprises poloxamers, poloxamine, ,hydroxypropyl methyl cellulose, drugs embedded liposomes and optionally maltodextrin.
  • the formulation helps in conversion of non-aqueous to aqueous form and masks the bitter taste.
  • the formulation can be used for other practically water-insoluble and water-soluble bitter drugs in addition to the present metformin formulation.
  • the formulation of the present invention is safe, cost-effective, and suitable for geriatric patients with difficulty in swallowing as the formulation is useful as liquid dosage form and does not induce insulin resistance on long term usage.
  • FIG 1 tabulates a formulation of the present invention according to an embodiment of the invention.
  • FIG 2 tabulates the results of the dissolution of metformin and the metformin hydrochloride form the formulation of the present invention.
  • FIG 3 tabulates the effect of the formulation of the present invention in exhibiting hypoglycemic activity in neonatal male Wistar rats.
  • FIG 4 tabulates the formulation of the present invention according to an embodiment of the invention.
  • Drug Resistance refers to the condition in which reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition.
  • Combination Therapy refers to use of two or more active ingredients in combination to treat a single disease.
  • Taste Masking refers to a perceived reduction of an undesirable taste that would otherwise exist for active pharmaceutical ingredients or drugs to achieve patient acceptability and compliance.
  • the present invention overcomes the drawbacks of the existing technologies by a formulation of combination therapy and with effective taste masking.
  • the present invention discloses a formulation with a combination of metformin HC1, teneligliptin, vitamin B12, levothyroxine sodium, atorvastatin, Poloxamer 407 or 188, sorbitol, sodium benzoate and water.
  • the formulation is prepared for oral administration.
  • FIG 1 tabulates the formulation of the present invention according to an embodiment of the invention.
  • the formulation is a combination therapy comprising metformin HC1 at a concentration in the range between 200 mg to 1000 mg as an active ingredient, teneligliptin at a concentration in the range between 10 mg to 40 mg, vitamin B12 at a concentration in the range between 0.0024 mg to 0.024 mg, levothyroxine sodium at a concentration in the range between 0.005 mg to 0.050 mg, atorvastatin or pravastatin at a concentration in the range between 5 mg to 10 mg, Poloxamer 407, 331 or 188 at a concentration in the range between 450 mg to 1500 mg, sorbitol at a concentration in the range between 100 mg to 300 mg, sodium benzoate and water.
  • Metformin HC1 used in the formulation is 6.66% to 33.33% w/v as hypoglycemic agent, which exhibits antidiabetic activity. Teneligliptin at 0.33% to 1.32 % w/v is used in combination with metformin HC1.
  • the formulation also comprises vitamin B12 at 0.0008% to 0.0008 % w/v.
  • metformin HC1 is associated with diabetic neuropathy. This is overcome by the formulation of the present invention with the use of vitamin B12, which improves the somatic symptoms such as pain and paresthesia. Thus, the combination of metformin HC1 with vitamin B12 reduces the risk of onset of diabetic neuropathy.
  • the combination of metformin hydrochloride and teneligliptin reduces blood glucose level by multiple mechanisms which also include the inhibition of human plasma DPP-4 activity and recombinant human DPP-4 activity in a concentration-dependent manner with half-maximal inhibitory concentrations.
  • the combination is also effective in improving the glycemic index and lipid profile in patients in diabetes.
  • the formulation further comprises levothyroxine sodium at 0.00016 % to 0.0016 % w/v.
  • the thyroid hormones are crucial for body's metabolism and energy expenditure. Low thyroid hormone levels are associated with higher Body Mass Index (BMI), which in turn is a risk factor for diabetes.
  • BMI Body Mass Index
  • the excessive thyroid hormone causes increased glucose production in the liver, rapid absorption of glucose through the intestine and increases insulin resistance.
  • the supplementation of levothyroxine sodium in the formulation overcomes the risk.
  • atorvastatin at 0.00165 % to 0.0133 % w/v
  • sorbitol at 3.33% to 10% w/v are used in the formulation.
  • the required quantity of sodium benzoate as preservative and water are used in the formulation.
  • the formulation of the present invention is a unique combination with antidiabetic agents and suitable excipients.
  • the presence of vitamin B12 and levothyroxine sodium in the formulation enhances the efficacy of metformin HC1.
  • Atorvastatin in the formulation reduces the insulin resistance by reducing triglycerides level and reduces the blood pressure.
  • the formulation may also comprise pravastatin, lovastatin or Fluvastatin in place of atorvastatin. The presence of these ingredients in the formulation exhibits additive effect for the treatment of diabetes.
  • the formulation of the present invention is prepared by cold mixing method of all the ingredients for two to three hours. This method reduces the overall cost of production of the formulation.
  • the formulation is prepared for oral administration.
  • the formulation comprises Poloxamer 407, Poloxamer 331 or Poloxamer 188 thus making it sustained release formulation.
  • the sustained release of the active ingredients thus resulting in delivery for a prolonged period of time with 12 to 24 hours with single dose and sustained release prevents rapid metabolism and elimination of the drug from the body shortly after administration.
  • the pharmacokinetics are improved due to the sustained release formulation.
  • the formulation is specifically for oral liquid dosage form to overcome the drawbacks associated with solid dosage form, which is difficult to swallow especially in pediatrics and geriatrics.
  • the formulation of the present invention is analyzed for antidiabetic activity and in reducing the reduction of blood glucose levels.
  • the formulation of the present invention is unique with respect to the combination of the ingredients used thus enhancing the biological activity.
  • the formulation of the present invention is analyzed for its in vitro drug release.
  • the dissolution rate of metformin HC1 is analyzed using the standard protocol using a Paddle type USP Type II dissolution test apparatus (Electro lab, ETC-11L).
  • the dissolution rate if analyzed using 900 mL 0.1N HC1 for 2h, followed by 7.4 pH phosphate buffer maintained at 50 rpm speed, 37 ⁇ 0.5°C.
  • FIG 2 tabulates the results of the dissolution of metformin and the metformin hydrochloride form the formulation of the present invention.
  • the in vitro drug release is analyzed up to 12 hours and the results indicated that metformin hydrochloride exhibited release of 93.263 % of metformin hydrochloride in 12 hours and interprets good dissolution profile.
  • Example 1 Effect of the formulation for antidiabetic activity in rat model of type of diabetes.
  • the formulation of the present invention is analyzed for its efficacy in antidiabetic activity by inducing hypoglycemia in Neonatal male Wistar rats with type 2 diabetes.
  • the study is conducted as per the CPSCEA guidelines for research in small animals.
  • the experimental procedures were approved by the Institutional Animal Ethics Committee (IAEC) and the ethical clearance certificate for the same has been obtained and appended.
  • IAEC Institutional Animal Ethics Committee
  • the maximum and minimum temperature and relative humidity in the experimental room was recorded once daily.
  • the rats were acclimatized to laboratory conditions for one week before commencement of the experiment.
  • the polypropylene cages had provision for water bottle holder and feed hopper with corn cobs as bedding material.
  • the rats were given diet including ad libitum, pelleted rodent feed (VRK nutrition solutions), high fat diet and water ad libitum (Aqua guard water in polypropylene bottles) except during experimentation.
  • Neonatal male Wistar rats of 1-2-day old were injected with Streptozotocin (STZ) at the dose of 90 mg/kg intraperitoneally, high fat diet to induce diabetes and allowed to grow for 8 weeks.
  • the diabetic rats are divided into three groups, each group containing six Wistar rats weighing between 150-250 g. A normal control group of 6 animals were also taken. Blood glucose was measured to confirm diabetes (above 200 mg/dL) and such animals were divided into the 3 groups of 6 each.
  • the overnight fasted rats were administered with vehicle alone, formulation of the present invention in the form of liquid administered orally and at a single dose of 100 mg/kg and standard Metformin (pure drug solution, orally administered at a single dose of 100 mg/kg).
  • the blood glucose was measured at 1, 2, 3, 4, 6, 8, 12 and 24 h after the administration to analyze the anti-diabetic activity of the formulation of the present invention.
  • FIG 3 tabulates the effect of the formulation of the present invention in exhibiting hypoglycemic activity in neonatal male Wistar rats.
  • the efficacy of the formulation on blood glucose levels is analyzed at 1, 2, 3, 4, 6, 8, 12 and 24 h after the administration of the formulation.
  • the efficacy of the hypoglycemic effect of the liquid formulation of the present invention is more than the standard metformin formulation. This indicates the synergistic effect of metformin HC1 with other ingredients namely teneligliptin, vitamin B12, levothyroxine sodium, atorvastatin, or pravastatin in the formulation.
  • the study also indicates the efficacy of the single dose of the liquid form of the formulation administered orally in inducing hypoglycemic effect thus exhibiting the anti diabetic activity in rat model.
  • the formulation allows the easy swallowing upon oral administration by masking the bitter taste of the liquid formulation thus reducing the nausea especially in geriatric or pediatric patients or other patients with difficulty in swallowing.
  • the taste masking of the present formulation is achieved using a unique formulation.
  • the formulation is an aqueous and taste masking conventional and sustained liquid, semi-solid, and solid dosage forms for water-soluble and water-insoluble bitter drugs.
  • FIG 4 tabulates the formulation of the present invention according to an embodiment of the invention.
  • the formulation for taste masking comprises Poloxamer or poloxamine at a concentration in a range between 3% and 37% w/v, Hydroxypropyl Methyl Cellulose (HPMC) at a concentration in a range between 0.1% and 2% w/v, liposomes at a concentration in a range between 0.1% and 3% w/v and optionally maltodextrin at a concentration in a range between 0% and 0.5 % w/v.
  • HPMC Hydroxypropyl Methyl Cellulose
  • the formulation of taste masking converts the non-aqueous to aqueous form and masks the bitter taste of the active pharmaceutical ingredient.
  • the formulation is useful for any practically water-insoluble and water-soluble bitter drugs.
  • the formulation of taste masking is prepared by a simple method which comprises a processing module, which does not require high heat thus avoiding the degradation of drug, the method is simple to prepare i.e., only mixing and is effective, and is inexpensive as required minimal manufacturing cost.
  • the method involves placing hydroxypropyl methylcellulose over a vacuum- forming mold in which indentations of the shape of the finished dosage forms are present.
  • the film is heated, and vacuum formed to give a film with a plurality of blisters depending on a planar upper surface.
  • Each blister is filled with the appropriate amount of core material prepared and a flat film of the same hydroxypropyl methylcellulose is attached to the planar upper surface of the vacuum-formed film by applying an adhesive to both the flat film and the planar upper surface and applying pressure to ensure a good seal.
  • the individual capsules are then separated and packed.
  • the formulation of taste masking is simple, cost-effective, and suitable for wide range of drugs in addition to the present formulation of metformin.
  • the taste masking formulation of the present invention is not only restricted to metformin formulation of the present invention but shall also be extended to other drugs and not limited to paracetamol, metronidazole, tofacitinib, alprazolam, amiloride, amlodipine, atenolol, benazepril, bisoprolol, captopril, ciprofloxacin, citalopram, clomipramine, desloratadine, diclofenac sodium, digoxin, diltiazem, doxazosin, ergotamine, finasteride, fluconazole, fluoxetine, fluvastatin, fluvoxamine, gabapentin, hydralazine, indapamide, ketotifen, lamivudine, levetiracetam, levothyroxine, limaprost, lisinopril, lorazepam, losartan, metoprolol,
  • the formulation delays the discharging of the active ingredient, sustains, and releases the active ingredient in small intestines thus minimizing the side effects caused by regular formulations, and has improved intake convenience being in a liquid dosage form especially for geriatric patients.
  • the formulation is unique with respect to the combination therapy comprising vitamin B12 and levothyroxine sodium that increases the therapeutic efficacy of antidiabetic agent.
  • the formulation is safe, cost-effective i.e., only one fourth of the existing formulations, elegant and does not induce any toxicity with improved pharmacokinetics parameters.
  • the formulation of the present invention is associated with good patient compliance, ease of ingestion, avoidance of pain etc thus making a potential medication for the treatment of diabetes.

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Abstract

The invention discloses the formulation, which is a combination therapy for treatment of type 2 diabetes in patients. The formulation comprises 200 mg to 1000 mg metformin HCl, 10 mg to 40 mg teneligliptin, 0.0024 mg to 0.024 mg vitamin B12, 0.005 mg to 0.050 mg levothyroxine sodium, 5 mg to 10 mg atorvastatin, 450 mg to 1500 mg Poloxamer 407 or 188, 100 mg to 300 mg sorbitol, sodium benzoate and water. The bitter taste of the aqueous formulation is masked by a formulation comprising 3 to 37 % w/v Poloxamer or poloxamine, 0.1 to 2 % w/v HPMC, 0.1 to 3% w/v liposomes and optionally maltodextrin. The formulation is safe, results in sustained release of drug for 24 hours and is suitable for oral administration in patients with type 2 diabetes.

Description

An oral liquid formulation of metformin, teneligliptin, vitamin B12, atorvastatin and levothyroxine for diabetes
Priority Claim [0001] This application claims priority from the provisional application numbered
202141014729 filed with Indian Patent Office, Chennai on 31st March 2021 entitled “An oral liquid formulation of metformin, teneligliptin, vitamin B12, atorvastatin and levothyroxine for diabetes and the provisional application numbered 202141061600 filed with Indian Patent Office, Chennai on 29th December 2021 entitled “ Aqueous conventional and sustained liquid, semi-solid and solid dosage forms for water and lipid soluble bitter drugs by using poloxamer, maltodextrin, poloxamine and liposomes ” entirety of which is expressly incorporated herein by reference.
DESCRIPTION OF THE INVENTION
Technical field of the invention [0002] The present invention relates to a formulation comprising metformin hydrochloride for the treatment of type 2 diabetes. More particularly, the invention discloses the formulation, which is a combination of metformin hydrochloride, teneligliptin, vitamin B12, levothyroxine sodium and atorvastatin in a liquid sustained dosage form for treatment of type 2 diabetes in patients. The formulation is suitable for oral administration even in patients with swallowing difficulty. The invention also discloses a composition of an aqueous and taste masking conventional and sustained liquid, semi-liquid, and solid dosage forms for water-soluble and water-insoluble bitter drugs. Background of the invention
[0003] Diabetes mellitus commonly known as diabetes is a metabolic disease that causes high blood glucose. The hormone insulin transfers glucose from the blood into the cells to be stored or used for energy. In case of diabetes, the body either does not produce enough insulin from pancreas or can’t effectively use the insulin it does make causing the higher blood glucose level.
[0004] There are different types of diabetes namely Type 1 diabetes, which is an autoimmune disease. The immune system attacks and destroys the cells in the pancreas, where insulin is synthesized. About 10% of the human population with diabetes has this type. Secondly, type 2 diabetes which occurs when the body becomes resistant to insulin, and glucose builds up in blood. Prediabetes occurs when blood glucose is higher than normal, but it’s not high enough for a diagnosis of type 2 diabetes. Finally, gestational diabetes is high blood glucose during pregnancy and shall be normalized post-delivery. Insulin-blocking hormones produced by the placenta cause this type of diabetes.
[0005] The risk factors for prediabetes and type 2 diabetes are similar. They include being overweight, a family history of diabetes, having a high-density lipoprotein (HDL) cholesterol level lower than 40 mg/dL or 50 mg/dL, a history of high blood pressure, having gestational diabetes or giving birth to a child with a birth weight of more than 9 pounds, a history of polycystic ovary syndrome (PCOS), being more than 45 years of age, having a sedentary lifestyle etc.
[0006] Type 2 diabetes mellitus is a chronic metabolic disorder in which prevalence has been increasing steadily all over the world. As a result of this trend, it is fast becoming an epidemic in some countries of the world with the number of people affected expected to double in the next decade due to increase in ageing population, thereby adding to the already existing burden for healthcare providers, especially in poorly developed countries. It is estimated that 366 million people had diabetes mellitus in 2011, by 2030 this would have risen to 552 million. The number of people with type 2 diabetes mellitus is increasing in every country with 80% of people with diabetes mellitus living in low- and middle-income countries.
[0007] Generally, diabetes is treated with medications and improved balance of diet and physical activity. Two therapeutic approaches to this problem have been developed namely Glucagon-like peptide 1 (GLP-1) analogues with increased half-lives and Dipeptidyl peptidase-IV inhibitor (DPP-IV) inhibitors, which prevent the breakdown of endogenous GLP-1 as well as GIP. Both the classes of agents have potential not only to normalize fasting and postprandial glucose levels but also to improve beta-cell functioning and mass.
[0008] The adipose tissue plays a crucial role in the pathogenesis of type 2 diabetes mellitus. This constitutes the framework for the analysis of the interplay between insulin resistance and beta-cell dysfunction in type 2 diabetes as well as between obesogenic environment and diabetes risk in the next decade.
[0009] Biguanides, of which metformin HC1 is the most commonly used in overweight and obese patients, suppresses hepatic glucose production, increases insulin sensitivity, enhances glucose uptake by phosphorylating GLUT-enhancer factor, increases fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal tract.
[0010] Taste is a crucial factor that determines the palatability of oral dosage form and patient compliance. It also gives a unique identity to a product and thereby provides a competitive advantage to a company, especially in the case of over-the-counter products. Taste-masking techniques are applied to mask or overcome the bitter or unpleasant taste of active pharmaceutical ingredients or drugs to achieve patient acceptability and compliance. Oral administration of bitter or unpleasant tasting drugs is often the biggest barrier for patient groups, such as pediatrics and geriatrics. Unless the active ingredient is tasteless or does not have any unpleasant taste, taste-masking plays a key role in the success of a final solid oral dosage form. [0011] The efficiency of taste-masking is often a key determinant for the success of specialized dosage forms such as orally disintegrating tablets and films, and chewable tablets. The mechanisms of taste-masking techniques often rely on two major approaches: the first is to add sweeteners, flavors, and effervescent agents to mask the unpleasant taste, and the second is to avoid the contact of bitter or unpleasant drugs with taste buds.
[0012] Polymers constitute a group of materials having a wide-ranging impact on modern pharmaceutical technology. Polymeric components provide the foundation for the advancement of novel drug delivery platforms, inter alia orodispersible films. Orodispersible films are thin, polymeric scraps intended to dissolve quickly when put on the tongue, allowing them to be easily swallowed without the necessity of drinking water, thus eliminating the risk of choking, which is of great importance in the case of pediatric and geriatric patients. Polymers are essential excipients in designing orodispersible films, as they constitute the backbone of these drug dosage forms. The type of polymer is of significant importance in obtaining the formulation of the desired quality. A variety of natural and synthetic polymers currently utilized in manufacturing of orodispersible films might be used alone or in a blend.
[0013] The Patent Application No. W02018033808A1 entitled “ Improved composition of teneligliptin and metformin HCl and method for preparing same ” relates to an improved pharmaceutical composition in the form of a coated oral tablet, with teneligliptin or the pharmaceutically acceptable salts thereof and metformin HCl or the pharmaceutically acceptable salts thereof, for the treatment of type 2 diabetes mellitus. The pharmaceutical composition is obtained by means of wet granulation, using metformin HCl ground to a fine powder and a low load of excipients consisting of a binder, in this case povidone, and magnesium stearate as a lubricant during compression. The use of ground metformin HCl considerably improves the compressibility of same, allowing operative conditions to be optimized. Compared with the two active ingredients separately and vehiculised in the form of coated tablets, the improved pharmaceutical composition comprising the combination of teneligliptin and metformin HCl show no differences in in vitro release (solution), and, moreover, improved the compressibility of the powder and the friability of the tablets. The features mentioned distinguish this improved composition from other compositions containing the same active ingredients and using more excipients.
[0014] The Patent Application No. IL158506A entitled “ Oral pharmaceutical form for a single daily intake combining a metformin HCl and at least one other antidiabetic active principle” discloses antidiabetic (type II diabetes) oral galenic form comprising an ' active principle A chosen from biguanides, metformin HCl being particularly preferred, A being combined with at least one other antihyperglycemic active principle B.
[0015] The Patent Application No. DE10360924A1 entitled “ Composition containing metformin, useful as antidiabetic, is formulated as water-soluble granules for administration, after dissolution, through a gastric tube ” discloses a composition containing metformin HCl as active agent and auxiliaries, is formulated as water-soluble granulate. An independent claim is also included for device for administering a (I) solution (as a drink), comprising a gastric tube that can be linked, through a connecting piece, to a container holding a predetermined dose of the (I) solution.
[0016] The Patent Application No. KR20060006469A entitled “ Oral antidiabetic composition comprising metformin HCl and glimepiride and the preparation method thereof relates to a pharmaceutical composition for treating oral diabetes comprising metformin HCl and glimepiride together with a pharmaceutically acceptable carrier. In addition, the present invention forms a wet granule with a disintegrant in metformin, glimepiride, and wet granules, and after the formation of granules by mixing another disintegrant, pharmaceutical disintegrators are included in both wet granulation and post granulation mixing.
[0017] The Patent Application No. US7767231B2 entitled “ Taste-masking pharmaceutical compositions discloses a pharmaceutical composition for oral administration suitable for the preparation of a ready-to-use suspension comprising coated particles comprising an active substance having an unpleasant and/or bitter taste, such as clarithromycin, and a suspension base comprising an osmotically active substance capable of providing a high osmolality to the admixture of the suspension base with an aqueous suspending medium in the ready-to-use suspension. The said ready-to-use suspension maintains its palatability over a prolonged period by those defined osmotic conditions.
[0018] The Patent Application No. WO2014194872A1 entitled “ Taste masking of water- soluble drugs using poloxamers” discloses taste-masked solid, semi-solid and liquid pharmaceutical formulations containing a water-soluble drug and poloxamer, and a new use of poloxamers as taste masking agents for water-soluble drugs.
[0019] The existing formulations may not be effective in all patients due to drug resistance and due to the mode of administration. Hence, there is a need for a formulation with a combination to enhance the antidiabetic activity. Further the existing metformin HC1 compositions are solid dosage forms but does not include effective mode of administration with sustained release for improved efficacy and pharmacokinetic profile.
Summary of the invention
[0020] In order to overcome the drawbacks of the state of art, the present invention provides a formulation for treatment of type 2 diabetes. The formulation, which is a combination of metformin hydrochloride, teneligliptin, vitamin B12, levothyroxine sodium and atorvastatin in suitable for liquid sustained dosage form.
[0021] The formulation of the present invention is a combination therapy comprising metformin HC1 at a concentration in the range between 200 mg to 1000 mg, teneligliptin at a concentration in the range between 10 mg to 40 mg, vitamin B12 at a concentration in the range between 0.0024 mg to 0.024 mg, levothyroxine sodium at a concentration in the range between 0.005 mg to 0.050 mg, atorvastatin or pravastatin at a concentration in the range between 5 mg to 10 mg, Poloxamer 407, 331 or 188 at a concentration in the range between 450 mg to 1500 mg, sorbitol at a concentration in the range between 100 mg to 300 mg, sodium benzoate and water. [0022] The presence of suitable excipients in the formulation as combination enhances the activity of metformin hydrochloride by exhibiting the synergistic effect.
[0023] The formulation is unique as it’s useful as liquid dosage form for single dose. The presence of vitamin B12 in the formulation reduces the risk of onset of diabetic neuropathy generally associated with use of metformin HC1. Similarly, vitamin B12 and levothyroxine sodium in the formulation enhances the efficacy of metformin HC1. The presence of statin in the formulation reduces the risk of insulin resistance by reducing triglycerides level and reduces the blood pressure. Hence, the combination of metformin HC1 with suitable other ingredients exhibited synergistic activity in anti-diabetic activity.
[0024] The dissolution study and the in vitro drug release of metformin HC1 is analyzed up to 12 hours and metformin hydrochloride exhibited release of 93.263 % in 12 hours and interprets good dissolution profile.
[0025] The formulation is compared with standard metformin in inducing the blood glucose levels in rat model of diabetes. The formulation at a single dosage of 100 mg/kg is effective than standard metformin reducing the blood glucose levels in rat model of diabetes.
[0026] The present invention also discloses an approach for taste masking the bitter drugs including metformin. The formulation comprises poloxamers, poloxamine, ,hydroxypropyl methyl cellulose, drugs embedded liposomes and optionally maltodextrin. The formulation helps in conversion of non-aqueous to aqueous form and masks the bitter taste. The formulation can be used for other practically water-insoluble and water-soluble bitter drugs in addition to the present metformin formulation.
[0027] The formulation of the present invention is safe, cost-effective, and suitable for geriatric patients with difficulty in swallowing as the formulation is useful as liquid dosage form and does not induce insulin resistance on long term usage. Brief description of drawings
[0028] FIG 1 tabulates a formulation of the present invention according to an embodiment of the invention.
[0029] FIG 2 tabulates the results of the dissolution of metformin and the metformin hydrochloride form the formulation of the present invention.
[0030] FIG 3 tabulates the effect of the formulation of the present invention in exhibiting hypoglycemic activity in neonatal male Wistar rats.
[0031] FIG 4 tabulates the formulation of the present invention according to an embodiment of the invention.
Detailed description of the invention
[0032] In order to more clearly and concisely describe and point out the subject matter of the claimed invention, the following definitions are provided for specific terms, which are used in the following written description.
[0033] The term “ Drug Resistance ” refers to the condition in which reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition.
[0034] The term “ Combination Therapy ” refers to use of two or more active ingredients in combination to treat a single disease.
[0035] The term “ Taste Masking ” refers to a perceived reduction of an undesirable taste that would otherwise exist for active pharmaceutical ingredients or drugs to achieve patient acceptability and compliance.
[0036] The present invention overcomes the drawbacks of the existing technologies by a formulation of combination therapy and with effective taste masking. [0037] The present invention discloses a formulation with a combination of metformin HC1, teneligliptin, vitamin B12, levothyroxine sodium, atorvastatin, Poloxamer 407 or 188, sorbitol, sodium benzoate and water. The formulation is prepared for oral administration.
[0038] FIG 1 tabulates the formulation of the present invention according to an embodiment of the invention. The formulation is a combination therapy comprising metformin HC1 at a concentration in the range between 200 mg to 1000 mg as an active ingredient, teneligliptin at a concentration in the range between 10 mg to 40 mg, vitamin B12 at a concentration in the range between 0.0024 mg to 0.024 mg, levothyroxine sodium at a concentration in the range between 0.005 mg to 0.050 mg, atorvastatin or pravastatin at a concentration in the range between 5 mg to 10 mg, Poloxamer 407, 331 or 188 at a concentration in the range between 450 mg to 1500 mg, sorbitol at a concentration in the range between 100 mg to 300 mg, sodium benzoate and water.
[0039] Metformin HC1 used in the formulation is 6.66% to 33.33% w/v as hypoglycemic agent, which exhibits antidiabetic activity. Teneligliptin at 0.33% to 1.32 % w/v is used in combination with metformin HC1. The formulation also comprises vitamin B12 at 0.0008% to 0.0008 % w/v. Generally, metformin HC1 is associated with diabetic neuropathy. This is overcome by the formulation of the present invention with the use of vitamin B12, which improves the somatic symptoms such as pain and paresthesia. Thus, the combination of metformin HC1 with vitamin B12 reduces the risk of onset of diabetic neuropathy.
[0040] The combination of metformin hydrochloride and teneligliptin reduces blood glucose level by multiple mechanisms which also include the inhibition of human plasma DPP-4 activity and recombinant human DPP-4 activity in a concentration-dependent manner with half-maximal inhibitory concentrations. The combination is also effective in improving the glycemic index and lipid profile in patients in diabetes. [0041] The formulation further comprises levothyroxine sodium at 0.00016 % to 0.0016 % w/v. The thyroid hormones are crucial for body's metabolism and energy expenditure. Low thyroid hormone levels are associated with higher Body Mass Index (BMI), which in turn is a risk factor for diabetes. The excessive thyroid hormone causes increased glucose production in the liver, rapid absorption of glucose through the intestine and increases insulin resistance. The supplementation of levothyroxine sodium in the formulation overcomes the risk. In addition, atorvastatin at 0.00165 % to 0.0133 % w/v, Poloxamer 407, 331 or 188 at 15% to 50 % w/v, sorbitol at 3.33% to 10% w/v are used in the formulation. Finally, the required quantity of sodium benzoate as preservative and water are used in the formulation.
[0042] The formulation of the present invention is a unique combination with antidiabetic agents and suitable excipients. The presence of vitamin B12 and levothyroxine sodium in the formulation enhances the efficacy of metformin HC1. Atorvastatin in the formulation reduces the insulin resistance by reducing triglycerides level and reduces the blood pressure. The formulation may also comprise pravastatin, lovastatin or Fluvastatin in place of atorvastatin. The presence of these ingredients in the formulation exhibits additive effect for the treatment of diabetes.
[0043] The formulation of the present invention is prepared by cold mixing method of all the ingredients for two to three hours. This method reduces the overall cost of production of the formulation.
[0044] The formulation is prepared for oral administration. The formulation comprises Poloxamer 407, Poloxamer 331 or Poloxamer 188 thus making it sustained release formulation. The sustained release of the active ingredients thus resulting in delivery for a prolonged period of time with 12 to 24 hours with single dose and sustained release prevents rapid metabolism and elimination of the drug from the body shortly after administration. As a result, the pharmacokinetics are improved due to the sustained release formulation. The formulation is specifically for oral liquid dosage form to overcome the drawbacks associated with solid dosage form, which is difficult to swallow especially in pediatrics and geriatrics.
[0045] The formulation of the present invention is analyzed for antidiabetic activity and in reducing the reduction of blood glucose levels. The formulation of the present invention is unique with respect to the combination of the ingredients used thus enhancing the biological activity.
[0046] The formulation of the present invention is analyzed for its in vitro drug release. The dissolution rate of metformin HC1 is analyzed using the standard protocol using a Paddle type USP Type II dissolution test apparatus (Electro lab, ETC-11L). The dissolution rate if analyzed using 900 mL 0.1N HC1 for 2h, followed by 7.4 pH phosphate buffer maintained at 50 rpm speed, 37 ± 0.5°C. Sol (5 mL) equivalent to the dose of the 500 mg for metformin, which was taken in a vial, placed in the dissolution vessel and for Metformin HC1, phosphate buffer at pH 6.8 was used where it was converted to a gel.
[0047] At regular intervals of time, an aliquot of 5 mL was withdrawn, filtered through a 45 pm membrane filter, and then replaced with a fresh medium of the same volume i.e., 1 mL taken and made to 10 mL. Lurther dilutions are made to obtain 10 pg / mL and then assayed 232 nm for Metformin HC1 using a UV-visible spectrophotometer.
[0048] FIG 2 tabulates the results of the dissolution of metformin and the metformin hydrochloride form the formulation of the present invention. The in vitro drug release is analyzed up to 12 hours and the results indicated that metformin hydrochloride exhibited release of 93.263 % of metformin hydrochloride in 12 hours and interprets good dissolution profile.
[0049] The following examples are offered to illustrate various aspects of the invention. However, the examples are not intended to limit or define the scope of the invention in any manner. Example 1: Effect of the formulation for antidiabetic activity in rat model of type of diabetes.
[0050] The formulation of the present invention is analyzed for its efficacy in antidiabetic activity by inducing hypoglycemia in Neonatal male Wistar rats with type 2 diabetes. The study is conducted as per the CPSCEA guidelines for research in small animals. The experimental procedures were approved by the Institutional Animal Ethics Committee (IAEC) and the ethical clearance certificate for the same has been obtained and appended.
[0051] The maximum and minimum temperature and relative humidity in the experimental room was recorded once daily. The rats were acclimatized to laboratory conditions for one week before commencement of the experiment. The polypropylene cages had provision for water bottle holder and feed hopper with corn cobs as bedding material. The rats were given diet including ad libitum, pelleted rodent feed (VRK nutrition solutions), high fat diet and water ad libitum (Aqua guard water in polypropylene bottles) except during experimentation.
[0052] Neonatal male Wistar rats of 1-2-day old were injected with Streptozotocin (STZ) at the dose of 90 mg/kg intraperitoneally, high fat diet to induce diabetes and allowed to grow for 8 weeks. The diabetic rats are divided into three groups, each group containing six Wistar rats weighing between 150-250 g. A normal control group of 6 animals were also taken. Blood glucose was measured to confirm diabetes (above 200 mg/dL) and such animals were divided into the 3 groups of 6 each. The overnight fasted rats were administered with vehicle alone, formulation of the present invention in the form of liquid administered orally and at a single dose of 100 mg/kg and standard Metformin (pure drug solution, orally administered at a single dose of 100 mg/kg). The blood glucose was measured at 1, 2, 3, 4, 6, 8, 12 and 24 h after the administration to analyze the anti-diabetic activity of the formulation of the present invention.
[0053] FIG 3 tabulates the effect of the formulation of the present invention in exhibiting hypoglycemic activity in neonatal male Wistar rats. The efficacy of the formulation on blood glucose levels is analyzed at 1, 2, 3, 4, 6, 8, 12 and 24 h after the administration of the formulation. The results indicated that the formulation of the present invention administered orally as a single dose at a dose of 100 mg/kg is effective in reducing the blood glucose levels in rats. The efficacy of the hypoglycemic effect of the liquid formulation of the present invention is more than the standard metformin formulation. This indicates the synergistic effect of metformin HC1 with other ingredients namely teneligliptin, vitamin B12, levothyroxine sodium, atorvastatin, or pravastatin in the formulation.
[0054] The study also indicates the efficacy of the single dose of the liquid form of the formulation administered orally in inducing hypoglycemic effect thus exhibiting the anti diabetic activity in rat model.
[0055] The formulation allows the easy swallowing upon oral administration by masking the bitter taste of the liquid formulation thus reducing the nausea especially in geriatric or pediatric patients or other patients with difficulty in swallowing.
[0056] The taste masking of the present formulation is achieved using a unique formulation. The formulation is an aqueous and taste masking conventional and sustained liquid, semi-solid, and solid dosage forms for water-soluble and water-insoluble bitter drugs.
[0057] FIG 4 tabulates the formulation of the present invention according to an embodiment of the invention. The formulation for taste masking comprises Poloxamer or poloxamine at a concentration in a range between 3% and 37% w/v, Hydroxypropyl Methyl Cellulose (HPMC) at a concentration in a range between 0.1% and 2% w/v, liposomes at a concentration in a range between 0.1% and 3% w/v and optionally maltodextrin at a concentration in a range between 0% and 0.5 % w/v.
[0058] The formulation of taste masking converts the non-aqueous to aqueous form and masks the bitter taste of the active pharmaceutical ingredient. The formulation is useful for any practically water-insoluble and water-soluble bitter drugs. [0059] The formulation of taste masking is prepared by a simple method which comprises a processing module, which does not require high heat thus avoiding the degradation of drug, the method is simple to prepare i.e., only mixing and is effective, and is inexpensive as required minimal manufacturing cost.
[0060] The method involves placing hydroxypropyl methylcellulose over a vacuum- forming mold in which indentations of the shape of the finished dosage forms are present. The film is heated, and vacuum formed to give a film with a plurality of blisters depending on a planar upper surface. Each blister is filled with the appropriate amount of core material prepared and a flat film of the same hydroxypropyl methylcellulose is attached to the planar upper surface of the vacuum-formed film by applying an adhesive to both the flat film and the planar upper surface and applying pressure to ensure a good seal. The individual capsules are then separated and packed.
[0061] The formulation of taste masking is simple, cost-effective, and suitable for wide range of drugs in addition to the present formulation of metformin.
[0062] The taste masking formulation of the present invention is not only restricted to metformin formulation of the present invention but shall also be extended to other drugs and not limited to paracetamol, metronidazole, tofacitinib, alprazolam, amiloride, amlodipine, atenolol, benazepril, bisoprolol, captopril, ciprofloxacin, citalopram, clomipramine, desloratadine, diclofenac sodium, digoxin, diltiazem, doxazosin, ergotamine, finasteride, fluconazole, fluoxetine, fluvastatin, fluvoxamine, gabapentin, hydralazine, indapamide, ketotifen, lamivudine, levetiracetam, levothyroxine, limaprost, lisinopril, lorazepam, losartan, metoprolol, montelukast, neostigmine, ondansetron, oxybutynin, paroxetine, perindopril, promethazine, propranolol, quetiapine, quinapril, ramipril, ranitidine, rivastigmine, salbutamol, sertraline, sumatriptan, terbinafine, theophylline, topiramate, tramadol, verapamil etc.
[0063] The formulation delays the discharging of the active ingredient, sustains, and releases the active ingredient in small intestines thus minimizing the side effects caused by regular formulations, and has improved intake convenience being in a liquid dosage form especially for geriatric patients.
[0064] The formulation is unique with respect to the combination therapy comprising vitamin B12 and levothyroxine sodium that increases the therapeutic efficacy of antidiabetic agent. The formulation is safe, cost-effective i.e., only one fourth of the existing formulations, elegant and does not induce any toxicity with improved pharmacokinetics parameters. The formulation of the present invention is associated with good patient compliance, ease of ingestion, avoidance of pain etc thus making a potential medication for the treatment of diabetes.

Claims

Claims We Claim,
1. A formulation of metformin for treatment of diabetes, the formulation comprising: a. metformin HC1 at a concentration in the range between 200 mg to 1000 mg; b. teneligliptin at a concentration in the range between 10 mg to 40 mg; c. vitamin B 12 at a concentration in the range between 0.0024 mg to 0.024 mg; d. levothyroxine sodium at a concentration in the range between 0.005 mg to 0.050 mg; e. a statin at a concentration in the range between 5 mg to 10 mg; f. Poloxamer at a concentration in the range between 450 mg to 1500 mg; g. sorbitol at a concentration in the range between 100 mg to 300 mg; h. sodium benzoate as preservative; and i. water wherein the formulation is prepared in a liquid dosage form for single dose oral administration.
2. The formulation as claimed in claim 1, wherein statin is selected from a group comprising atorvastatin, pravastatin, lovastatin or Fluvastatin.
3. The formulation as claimed in claim 1, wherein the formulation with combination of metformin HC1 and teneligliptin exhibits synergistic effect in reducing the risk of onset of diabetic neuropathy.
4. The formulation as claimed in claim 1, wherein vitamin B12 and levothyroxine sodium in the formulation enhances the efficacy of metformin HC1.
5. The formulation as claimed in claim 1, wherein Poloxamer is selected from a group comprising Poloxamer 407, Poloxamer 331 or Poloxamer 188.
6. The formulation as claimed in claim 1, wherein the formulation results in prolonged period with 12 to 24 hours of sustained release of metformin hydrochloride.
7. The formulation as claimed in claim 1, wherein metformin HC1 exhibited improved dissolution rate of 93.263 % in 12 hours.
8. The formulation as claimed in claim 1, wherein the formulation is effective than standard metformin reducing glucose levels in rat model of diabetes.
9. The formulation as claimed in claim 1, wherein the aqueous formulation is taste masked using a formulation comprising Poloxamer or poloxamine at a concentration in a range between 3% and 37% w/v, Hydroxypropyl Methyl Cellulose (HPMC) at a concentration in a range between 0.1% and 2% w/v, drugs embedded liposomes at a concentration in a range between 0.1% and 3% w/v and optionally maltodextrin at a concentration in a range between 0% and 0.5 % w/v.
10. The formulation as claimed in claim 1, wherein the taste masking formulation overcomes the bitter taste and unpleasantness of the formulation thus improving patient compliance during oral administration.
PCT/IB2022/052354 2021-03-31 2022-03-16 An oral liquid formulation of metformin, teneligliptin, vitamin b12, atorvastatin and levothyroxine for diabetes WO2022208216A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010271178B2 (en) * 2009-07-10 2015-10-22 Linzy O. Scott Iii Methods and compositions for treating thyroid-related medical conditions with reduced folates
WO2018148206A1 (en) * 2017-02-10 2018-08-16 Temple Otorongo Llc Treatment of diabetes and associated metabolic conditions with epigenetic modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010271178B2 (en) * 2009-07-10 2015-10-22 Linzy O. Scott Iii Methods and compositions for treating thyroid-related medical conditions with reduced folates
WO2018148206A1 (en) * 2017-02-10 2018-08-16 Temple Otorongo Llc Treatment of diabetes and associated metabolic conditions with epigenetic modulators

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