WO2019151964A2 - Formulations de saxagliptine à délitement buccal - Google Patents

Formulations de saxagliptine à délitement buccal Download PDF

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Publication number
WO2019151964A2
WO2019151964A2 PCT/TR2018/050869 TR2018050869W WO2019151964A2 WO 2019151964 A2 WO2019151964 A2 WO 2019151964A2 TR 2018050869 W TR2018050869 W TR 2018050869W WO 2019151964 A2 WO2019151964 A2 WO 2019151964A2
Authority
WO
WIPO (PCT)
Prior art keywords
orally disintegrating
sodium
saxagliptin
disintegrating pharmaceutical
super
Prior art date
Application number
PCT/TR2018/050869
Other languages
English (en)
Other versions
WO2019151964A3 (fr
Inventor
Ali TÜRKYILMAZ
Gülcan KAPLAN
Nur PEHLIVAN AKALIN
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2019151964A2 publication Critical patent/WO2019151964A2/fr
Publication of WO2019151964A3 publication Critical patent/WO2019151964A3/fr

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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
    • A61K31/33—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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to an orally disintegrating pharmaceutical formulation comprising saxagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • DPP-IV dipeptidyl peptidase IV
  • GLP-1 glucagon like peptide-1
  • DPP-IV inhibitors also commonly known as gliptins, competitively inhibit the enzyme DPP-IV, thereby increasing the endogenous concentration of GLP-1 , which further augments insulin secretion and improves the glycemic profile of patients with diabetes.
  • DPP-IV inhibitors such as saxagliptin, sitagliptin, vildagliptin, teneligliptin, alogliptin, and linagliptin are available as conventional tablet dosage forms.
  • Conventional tablet dosage forms constitute a preferred route of administration but certain groups of patients including geriatric, bed-ridden, uncooperative, nauseated, on reduced water intake, and patients having dysphagia, difficulty in swallowing, encounter problems while taking these dosage forms.
  • patients while travelling may have little or no access to water, limiting the use of conventional tablet dosage forms.
  • As antidiabetic drugs are prescribed chronically, such a problem could lead to a high level of patient non-compliance.
  • oral dispersible compositions provide the best alternative over conventional tablet dosage forms. Oral dispersible compositions which rapidly disintegrate on contact with saliva or in a small amount of water, offer increased convenience and ease of administration with the potential to achieve better patient compliance.
  • Saxagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor used for the treatment of type 2 diabetes mellitus.
  • DPP-IV dipeptidyl peptidase IV
  • U.S. Patent No. 6,395,767 discloses the compound saxagliptin.
  • saxagliptin is an unstable compound and it can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. This cyclization reaction can occur both in solid state and solution state.
  • the challenge of minimizing or preventing the cyclization reaction during manufacture of saxagliptin formulations is particularly significant because saxagliptin is a low dose drug, which is typically administered in dosage forms containing 2.5 or 5 mg of the drug, and hence the ratio of excipients to drug is high.
  • ODTs are solid dosage forms containing active ingredients which disintegrate rapidly through buccal mucosa. It is desirable in the treatment of a number of diseases including pediatric and geriatric treatments.
  • it is not easy to develop orally disintegrating formulations for all active agents because of several different reasons and requirements such as disintegration, stability, compressibility and taste masking.
  • Dosage form must disintegrate in the oral cavity with the existence of saliva in a short period of time. So, those compositions should have a porous structure.
  • Orally disintegrating tablets are usually pressed with lower compression forces than conventional tablets to obtain a higher porosity. However, these porous characteristics tend to be very sensitive to humidity and may be lead to stability problems.
  • the orally disintegrating tablet formulation of saxagliptin needs to be adapted in particular by a careful excipient selection give a suitable porous structure with suitable disintegrating time and high stability.
  • compositions are designed to rapidly disintegrate as the drug comes in direct contact with the tongue, it remains a challenge to the formulators to effectively mask the taste of bitter drugs such as saxagliptin inhibitors to increase the acceptability for these compositions.
  • compositions of saxagliptin thereof to achieve desired dissolution profile and release kinetic while overcoming stability and content uniformity problems.
  • the present invention teaches orally disintegrating compositions of a DPP-IV inhibitor with an acceptable taste.
  • the present invention relates to an orally disintegrating pharmaceutical formulation comprising saxagliptin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • saxagliptin or a pharmaceutically acceptable salt used in this present invention is saxagliptin hydrochloride.
  • Saxagliptin used in the composition of the present invention may be present in its crystalline form, amorphous form, anhydrous form, hydrate form, or mixtures thereof. According to this embodiment, saxagliptin or a pharmaceutically acceptable salt thereof is present in an amount of between 0.10 to 90.00 %, preferably between 0.50 to 50.00 % and more preferably it is 1 .00 to 20.00 % by weight of total formulation.
  • saxagliptin or a pharmaceutically acceptable salt thereof is present in an amount of between 1 mg and 20 mg, preferably 1 mg and 15 mg and more preferably it is between 1 mg and 5 mg.
  • the orally disintegrating formulation of saxagliptin or pharmaceutically acceptable salt thereof is disintegrated in less than 1 min.
  • the orally disintegrating formulation of this present invention comprises one or more pharmaceutically acceptable excipient selected from the group comprising super-disintegrants, taste masking agents, diluents, glidants, lubricants, binders, glidants, sweeteners, flavouring agents, acidifying agents or alkalizing agents or mixtures thereof.
  • the formulation comprises at least two super-disintegrants.
  • suitable amount of the super- disintegrants is between 0.01 to 10.00 % and preferably 0.01 to 5.00 % and more preferably 0.10 to 5.00 by weight of total formulation.
  • synergistically the ratio of saxagliptin to super-disintegrant also affects the compressibility.
  • the certain ratio of saxagliptin to super-disintegrants is in the range of between 0.01 and 5.00, preferably 0.02 and 2.00 and more preferably 0.2 and 1 .00.
  • the term“super-disintegrant” is defined as the pharmaceutical ingredient that provides improved compressibility, stability as well as achieves disintegration substantially faster than the conventional disintegrants.
  • the term “super-disintegrant” is selected from the group comprising crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), povidone, alginic acid and alginates, cross-linked alginic acid, sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, soy polysaccharide, guar gum, gellan gum, xanthan gum, magnesium alumina silica, polyacrylin potasium, poloxamer, sodium dodecyl sulphate, sodium lauryl sulphate, calcium silicate, sodium glycine carbonate or ion exchange resins or mixtures thereof.
  • the super-disintegrants are selected from crospovidone, croscarmellose sodium or mixtures thereof.
  • Suitable taste-masking agents may include but not limited to PVA (polyvinyl alcohol) based coating, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), butyl methacrylate and methyl methacrylate (Eudragit E 100) (Poly(butyl methacrylate-co-(2- demethylaminoeethyl)methacrylate-co-methyl methacrylate)), ethylcellulose dispersions (Surelease), Kerry-HPC, polyethylene glycol, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide, talc or polymethylmetacrylate copolymers (Eudragit) or mixtures thereof.
  • PVA polyvinyl alcohol
  • Kollicoat IR polyvinyl alcohol-polyethylene glycol copolymers
  • Suitable diluents are selected from the group comprising mannitol, xylitol, microcrystalline cellulose (MCC), lactose, corn starch dibasic calcium phosphate, xylitol, spray-dried lactose, sorbitol, sucrose, trehalose, isomalt, LudiFlash® (mannitol, crospovidon and polivinyl acetate), starch, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, dicalcium sulfate, sodium chloride, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate, pregelatinized starch, lactose monohydrate, sodium carbonate, sodium bicarbonate, isomalt, heavy magnesium carbonate, maltodextrine, mixture of sucrose - maltodextrine, dextrose, lactitol, calcium carbonate,
  • Content uniformity problem of the active agent is solved by using diluent. It’s important to choose diluent and use the diluent in a specific amount for providing a good uniformity of content and avoiding stability problems. Since the composition has porous characteristics, it’s sensitive to humidity and fragility which may be lead to stability problems. Furthermore, this stability problem becomes a big challenge due to cyclization reaction problem of saxagliptin.
  • the diluent is mannitol.
  • the diluent is in amount of between 50.00% and 90.00%, preferably 60.00% and 80.00% and more preferably between 65.00% and 75.00% by weight of total formulation.
  • Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, sodium lauryl sulphate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.
  • the lubricant is magnesium stearate.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone (PVP) (Kollidon) (povidone K30), carnauba wax, hydroxypropyl methyl cellulose (FIPMC), pullulan, polymeth acrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and other cellulose derivatives, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and their copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, chitosan, cellulose acetate phthalate, hydroxypropyl starch,
  • Suitable glidants are selected from the group comprising colloidal anhydrose silica, colloidal silicon dioxide (Aerosil), talc, aluminum silicate, powdered cellulose, calcium phosphate tribasic, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate or mixtures thereof.
  • the glidant is colloidal silicon dioxide.
  • Suitable sweeteners may include but not limited to sucralose, erythritol, thaumatin, mogroside, inuline, acesulfame-K, aspartame, saccharin or its sodium and calcium salts, sodium cyclamate, sucrose, fructose, glucose, sorbitol, menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape or mixtures thereof.
  • the sweetener is sucralose.
  • the sweetener is present in an amount of between 0.01% and 5.00% by weight of total formulation.
  • Taste is one of the most important parameters governing patient compliance. This parameter becomes more evident since the pharmaceutical composition is in the form of orally disintegrating tablets. Using a sweetener improves patient compliance. According to prior art, it is known that aspartame is used mostly as sweetener but contradictory to the prior art we have found that the effect of sucralose as a sweetener in this formulation, not only helped to improve its taste but also increased the efficacy and the conveniency of the formulation because of its positive effects over the glycemic index.
  • sucralose has an important role in this aspect and even if it is used in low amounts it has a synergistic taste improvement with mannitol which is also very important issue in orally disintegrating tablet formulations.
  • Suitable flavouring agents may include but not limited menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape etc. or mixtures thereof.
  • flavouring agent is peppermint.
  • the flavouring agent is present in an amount of between 0.0%1 and 5.00% by weight of total formulation.
  • Suitable acidifying agents may include but not limited to citric acid, fumaric acid, adipic acid, acetic acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, sulfuric acid, tartaric acid or mixtures thereof.
  • Suitable alkalizing agents may include but not limited to sodium bicarbonate, sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium carbonate, sodium borate, sodium hydroxide, trolamine or mixtures thereof.
  • orally disintegrating formulations comprises; a. 0.10 to 20.00 % saxagliptin
  • flavouring agent e. 0.10 to 5.00 %
  • Example 1 Orally disintegrating tablet
  • Example 2 Orally disintegrating tablet
  • Example 3 Orally disintegrating tablet
  • compositions mentioned above are prepared by following these steps:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique à délitement buccal, comprenant de la saxagliptine ou un sel pharmaceutiquement acceptable de celle-ci, et un ou plusieurs excipients pharmaceutiquement acceptables.
PCT/TR2018/050869 2017-12-26 2018-12-24 Formulations de saxagliptine à délitement buccal WO2019151964A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/21700 2017-12-26
TR2017/21700A TR201721700A2 (tr) 2017-12-26 2017-12-26 Saksagli̇pti̇ni̇n ağizda dağilan formülasyonlari

Publications (2)

Publication Number Publication Date
WO2019151964A2 true WO2019151964A2 (fr) 2019-08-08
WO2019151964A3 WO2019151964A3 (fr) 2019-10-31

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PCT/TR2018/050869 WO2019151964A2 (fr) 2017-12-26 2018-12-24 Formulations de saxagliptine à délitement buccal

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TR (1) TR201721700A2 (fr)
WO (1) WO2019151964A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021262114A1 (fr) * 2020-06-23 2021-12-30 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de comprimé à désintégration orale comprenant de la sitagliptine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114869904B (zh) * 2022-05-09 2023-10-20 广州汉光药业股份有限公司 复方维生素自乳化给药系统及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021262114A1 (fr) * 2020-06-23 2021-12-30 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de comprimé à désintégration orale comprenant de la sitagliptine

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Publication number Publication date
WO2019151964A3 (fr) 2019-10-31
TR201721700A2 (tr) 2019-07-22

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