WO2023079445A1 - Composition pharmaceutique de vitamine b12 à faible dose - Google Patents

Composition pharmaceutique de vitamine b12 à faible dose Download PDF

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Publication number
WO2023079445A1
WO2023079445A1 PCT/IB2022/060539 IB2022060539W WO2023079445A1 WO 2023079445 A1 WO2023079445 A1 WO 2023079445A1 IB 2022060539 W IB2022060539 W IB 2022060539W WO 2023079445 A1 WO2023079445 A1 WO 2023079445A1
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WIPO (PCT)
Prior art keywords
vitamin
composition
pharmaceutical composition
prepared
low dose
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PCT/IB2022/060539
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English (en)
Inventor
Swapnil Shivajirao KOLTE
Vinayak Dinkar Kadam
Subhash Pandurang Gore
Vijaya Kumar Thommandru
Govind Dnyanoba Ausekar
Girij Pal Singh
Radhakrishna Bhikaji Shivdavkar
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Lupin Limited
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Publication of WO2023079445A1 publication Critical patent/WO2023079445A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials

Definitions

  • the present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising low dose vitamin B12 with one or more suitable pharmaceutically acceptable excipients and methods of making such composition.
  • the invention relates to a solid oral pharmaceutical composition of low dose vitamin B12 with an improved content uniformity of vitamin B12 in the composition and use of such composition for the treatment of vitamin B12 deficiency.
  • Vitamin B 12 is a water-soluble vitamin. It is a coordination complex of cobalt; also known as cobalamin. It is the largest and most structurally complex of the eight water-soluble B vitamins. Vitamin B 12 is a class of cobalt and corrin ring molecules that possess vitamin activity. The sixth coordination site of the corrin ring is either a cyano group ( — CN), a hydroxyl group ( — OH), a methyl group ( — CH3) or a 5'- deoxyadenosyl group, creating four forms of vitamin B12, including, cyanocobalamin, hydroxocobalamin, methylcobalamin, and adenosylcobalamin.
  • vitamin B12 Human or plants cannot synthesize vitamin B12, but microbes can synthesize it.
  • Natural source of vitamin B12 is from animal origin food. A lower than normal absorption of vitamin B12 can be compensated by an increased intake of vitamin B12. Gastrointestinal absorption of vitamin B12, from food or supplements, depends on the presence of enough intrinsic factor and calcium ions. Adenosylcobalamin and methylcobalamin are the active forms of vitamin B12 in humans.
  • Vitamin B 12 is important for production of the DNA needed to make red blood cell. Deficiency of vitamin B 12 causes megaloblastic anemia, pernicious anemia that result in pale skin, weakness and fatigue. In addition, vitamin B12 plays an important role in the production of myelin, which insulates nerves and is critical to nervous system function. The general daily recommendation for adults is vanes from 0.4 mcg to 2.4 mcg depending upon the age. Pregnant and breastfeeding women would require higher doses.
  • Overdose of vitamin B12 causes various side effect such as nausea, vomiting, increase risk of blood cancer, severe allergic reaction, and diarrhea. There is a need to develop a composition of low dose vitamin B 12 to balance the safety risk and benefit ratio.
  • Vitamin B12 is highly sensitive to light and moisture. Further, the development of compositions of low dose of vitamin B12 presents technical and economic challenges that are not present for compositions with higher dose of Vitamin B 12.
  • WO 2021102053 discloses method of supplementing Vitamin B 12 and composition for the cyclical provision of a vitamin B12 compound in a dosing regimen.
  • WO 2020254396 discloses the method of improving the uniformity of content of vitamin B12 when manufacturing a fixed dose combination (FDC) that comprises a very small amount of vitamin B12 and, in comparison, a very high amount of an API that is known to decrease the serum vitamin B12 level of patients.
  • the application provides the composition that uses spray dried vitamin B12 in order to improve the content uniformity.
  • CN 109820831 cites the problem concerning homogeneity for making methylcobalamin dispersible tablets.
  • the application proposes the use preprocessing methylcobalamin with excipient and to make pellets by wet granulation process for the preparation of methylcobalamin dispersible tablets having dose of 0.5mg.
  • CN 112022826 discloses disadvantages of wet granulation technique to make the composition as the process is complicated, create content difference among particles and increase the risk of degradation of methylcobalamin.
  • the application offers to use the direct compression process to make the composition with 0.5% w/w methylcobalamin as an active with better content uniformity.
  • CN 106236719 discloses the stability issues with methylcobalamin composition prepared by wet granulation technique and suggests going for dry granulation to make composition of oral methylcobalamin 0.01-1%.
  • CN 109512787 A discloses the stability issues of methylcobalamin and discloses to make a solid dispersion of vitamin B 12 and macromolecule carrier such as Gelucire to improve bioavailability and to improve the stability of vitamin B12.
  • the present invention provides a solid oral pharmaceutical composition of low dose vitamin B12 that overcomes the challenges and problems associated with formulating and manufacturing low-dose vitamin B 12 dosage forms such as handling of active, content uniformity of dosage form.
  • the present invention provides a solid oral pharmaceutical composition comprising low dose vitamin B12 with an improved content uniformity of vitamin B12 wherein the composition is prepared by top spray granulation.
  • the composition of the invention has better content uniformity of vitamin B12 in comparison to the composition of vitamin B12 prepared by other techniques of wet granulation i.e. with the use of rapid mixer granulator.
  • the present invention relates to a solid oral pharmaceutical composition of vitamin B12 and a process of manufacturing such composition.
  • the present invention relates to a solid oral pharmaceutical composition of low dose vitamin B12 and methods of making such composition.
  • the invention provides a solid oral pharmaceutical composition of low dose vitamin B12 with an improved content uniformity of vitamin B12 in the composition.
  • Vitamin B12 shows various challenges for maintaining the content uniformity of it in the pharmaceutical composition when used in low dose.
  • low dose vitamin B12 oral dosage compositions prepared by top spray granulation, spray drying and solvent evaporation techniques ensures content uniformity than formulation prepared by conventional methods of granulation such as rapid mixing granulation (RMG).
  • RMG rapid mixing granulation
  • the pharmaceutical composition comprising low dose of Vitamin B 12 and one or more suitable pharmaceutically acceptable excipients exhibits improved content uniformity of vitamin B12 when the composition is prepared by using top spray granulation.
  • the invention is directed to a pharmaceutical composition of low dose of vitamin B12 i.e. lower than 5 mcg.
  • dose of vitamin B12 is 2.1 mcg or 2.2 mcg or 2.3 mcg or 2.4 mcg or 2.5 mcg or 2.6 mcg, 2.7 mcg.
  • Most preferred dose of vitamin B 12 is 2.4 mcg.
  • the invention is directed to a solid oral pharmaceutical composition comprising a low dose of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using top spray granulation.
  • the invention is directed to a solid oral pharmaceutical composition comprising 2.4 mcg of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using top spray granulation.
  • the invention is directed to a solid oral pharmaceutical composition comprising a low dose of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using solvent evaporation technique.
  • the invention is directed to a solid oral pharmaceutical composition comprising 2.4 mcg of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using solvent evaporation technique.
  • the invention is directed to a solid oral pharmaceutical composition comprising a low dose of vitamin B12 and one or more suitable pharmaceutically acceptable excipients wherein the composition is prepared by using spray drying.
  • the invention is directed to a solid oral pharmaceutical composition comprising 2.4 mcg of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using spray drying.
  • the pharmaceutical composition comprises vitamin B12 as an active not more than 1% of total weight of dosage form.
  • the pharmaceutical composition comprises vitamin B 12 and one or more pharmaceutically acceptable excipients in a ratio 0.004:99.996.
  • composition of the invention can be administered alone or as a fixed dose combination with other therapeutic agent or as part of dosing regimen such as oral contraceptive.
  • the pharmaceutical composition of the invention can be administered in the form of kit.
  • the herein described pharmaceutical composition form may comprise more than one active pharmaceutical ingredients (APIs).
  • the pharmaceutical composition of the invention comprises preferably only one active pharmaceutical ingredient i.e. vitamin B 12 and one or more suitable pharmaceutically acceptable excipient.
  • “Vitamin B 12” also known as methylcobalamin.
  • “low dose vitamin B 12” can be defined as relatively low doses of vitamin B12 compound when compared to current vitamin B12 supplementation regimens. Based on a per-dosage (and, typically, per day) basis e.g., by administering less than 5 mcg a day, less than 4 mcg a day, or less than about 3 mcg of a vitamin B12 compound a day, such as about 2-5 mcg/day or 2-3 mcg/day. Most preferably the dose is 2.4 mcg.
  • solid pharmaceutical dosage form or “pharmaceutical composition” or “pharmaceutical formulation” as used herein refers to a dosage form such as a tablet, a capsule, granules and/or a powder. Powders or granules, such as preparing an oral solution are typically packaged in a sachet or a stick-pack. Alternatively, powders may be filled into two-piece capsules (e.g. gelatine capsules size 0, 00 or 000).
  • the term “solid pharmaceutical dosage form” refers to a solid oral pharmaceutical dosage form selected from the group consisting of tablets, capsules, granules and powders. In another embodiment, the term “solid pharmaceutical dosage form” refers to a compressed tablet.
  • the term ' content uniformity' as used herein ensures that a consistent dose of an active pharmaceutical ingredient is maintained in each individual dosage form (e.g. capsule, tablet or sachet).
  • content uniformity is determined. To do so, multiple e.g. capsules or tablets are selected at random and a suitable analytical method is applied to assay the individual content of the active pharmaceutical ingredient in each capsule or tablet. According to European and US pharmacopoeia, from the obtained random tablet assay analysis, a relative standard deviation (RSD) and an acceptance value (AV) should be calculated. The percentage assay of randomly selected tablet should be in range between 90%-120%. The lower the RSD, the better the content uniformity. The calculated acceptance value should be lower than 15.
  • assay content, RSD and AV are preferably calculated as set out in "The United States pharmacopeia", 37th revision, physical tests, Uniformity of Dosage Units.
  • content uniformity of vitamin B 12 ensures that a vitamin B12 is uniformly distributed throughout the tablet even if the dose is low. Samples or tablets are randomly selected to determine the content in the dosage form by using suitable analytical methods.
  • the term “granulation “as used herein defines a process of agglomeration of fine powder particles. It improves flow properties, compactability, compressibility of powders and prevents segregation of the individual constituents of a mixture.
  • the pharmaceutical composition of the invention is prepared by different granulation technique such as top spray granulation, spray granulation and/or solvent evaporation technique. Most preferred technique is top spray granulation.
  • fluid bed or “top spray granulation” as used herein is a single step, enclosed process wherein mixing, granulation and drying can be achieved in the same equipment.
  • granulation is achieved by suspending the powders in a stream of fluidized air and spraying the binder solution from nozzles situated above the powder bed, opposite to the airflow.
  • Top spray granulation provides multiple advantages to the formulators including reduced process time and equipment, and uniform drying and granulation of the powder mixture. Additionally, formation of porous granules using a fluidized bed processor (FBP) facilitates wicking of liquids in tablets, thereby leading to quick in-vivo disintegration and dissolution.
  • FBP fluidized bed processor
  • solvent evaporation as used herein is well known technique in the art and is used for the preparation of premix. In this method solvent gets evaporated from drug and excipient solution/dispersion to form drug excipient premix. This method involves the volatile solvent, which is able to dissolve the drug and excipient, may remain in solution or dispersion form. Preferred solvents are of low boiling points.
  • spray drying is also a well-known technique in the art that is also used for the preparation of drug/excipient premix.
  • drug is dissolved in a solvent while excipients/carriers can be in solution form or dispersion form.
  • This solution/dispersions sprayed in to the hit zone of air/Nitrogen at high temperature resulting in to instantaneous drying of the solution in to solid powder.
  • This technique creates homogenous product while controlling particle size and morphology and the evaporation process is instantaneous making it suitable for heat- sensitive products and it is a highly automatable, scalable process.
  • excipient includes but not limited to solvent, diluent, filler, binder, disintegrants, lubricant, carrier, coating agent, acidity regulators, firming agents, release agents, etc. and the like, e.g., a pharmaceutically acceptable excipient that is conventional in the art.
  • solvent refers to any aqueous or non-aqueous liquid material where it used to dissolve or disperse active ingredient partially or completely.
  • aqueous solvent such as water or aqueous buffer
  • non-aqueous solvent such as ethanol, propylene glycol.
  • binder as used herein include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, povidone, waxes, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylalcohol (PVA) and the like including any combination of suitable binders.
  • binder is povidone. Binder is present in concertation range 1-15% w/w of total composition, preferably 5-5%.
  • diluent refers to any suitable soluble, pharmaceutically acceptable excipient such as anhydrous lactose, lactose monohydrate, mannitol, or an insoluble, pharmaceutically acceptable excipient such as microcrystalline cellulose or dicalcium phosphate and the like including any combinations thereof.
  • diluent is lactose monohydrate.
  • glidanf and “lubricant” as used herein include as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol.
  • disintegrant as used herein include, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, methyl-cellulose, agar, bentonite, xanthan gum and the like.
  • pharmaceutical composition comprises Vitamin B 12 as an active not more than 1% of total weight of composition.
  • Vitamin B 12 and excipient are present in a ratio 0.5:99.5; 1:99; 0.1:99.9; 0.05:99.95; 0.004:99.996, 0.003:99.997, 0.002:99.998. Most preferable ratio is 0.004:99.996.
  • invention relates to a solid pharmaceutical composition of vitamin B12 and a process of manufacturing such composition. More particularly, the invention relates to a solid oral pharmaceutical composition of low dose vitamin B 12 and methods of making such composition with an improved content uniformity of vitamin B12 in the composition.
  • invention provides a low dose vitamin B12 oral dosage compositions prepared by top spray granulation, spray drying and solvent evaporation technique that ensures content uniformity than formulation prepared by conventional methods of granulation such as rapid mixing granulation (RMG). More preferably, the solid oral pharmaceutical composition comprising low dose of vitamin B12 and one or more suitable pharmaceutically acceptable excipients exhibits improved content uniformity of vitamin B12 when the composition is prepared by using top spray granulation.
  • RMG rapid mixing granulation
  • invention provides a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising 2.4 mcg of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using top spray granulation.
  • the invention is directed to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising 2.4 mcg of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using solvent evaporation technique.
  • the invention is directed to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising 2.4 mcg of vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using spray drying.
  • the invention provides a solid oral pharmaceutical composition of vitamin B 12, wherein the amount of vitamin B 12 in the composition is less than 1% w/w of total composition, more preferably less than 0.5 w/w of total composition and most preferably 0.004% w/w of total composition.
  • inventions provide a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using top spray granulation and the amount of vitamin B12 in the composition is less than 1% w/w of the total composition, more preferably less than 0.5 w/w of the total composition and most preferably 0.004% w/w of the total composition.
  • composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using top spray granulation and the amount of vitamin B12 in the composition is 0.004% w/w of the total composition.
  • inventions provide a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using solvent evaporation technique and the amount of vitamin B12 in the composition is less than 1% w/w of the total composition, more preferably less than 0.5 w/w of the total composition and most preferably 0.004% w/w of the total composition.
  • invention provides a solid oral pharmaceutical composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using solvent evaporation technique and the amount of vitamin B12 in the composition is 0.004% w/w of the total composition.
  • a solid oral pharmaceutical composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using spray drying and the amount of vitamin B12 in the composition is less than 1% w/w of the total composition, more preferably less than 0.5 w/w of the total composition and most preferably 0.004% w/w of the total composition.
  • composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein the composition is prepared by using spray drying and the amount of vitamin B12 in the composition is 0.004% w/w of the total composition.
  • vitamin B12 administered as continuous or non- continuous typical cyclic administration in combination with other active as per defined treatment period basis by delivering a maximum of 50 mcg vitamin B12 compound/month, such as a maximum of about 40 mcg/month, about 35 mcg/month, or about 30 mcg/month, for example, about 15-45 mcg/month, about 17.5-37.5 mcg/month, about 20-35 mcg/month, or about 20-30mcg/month.
  • a maximum of 50 mcg vitamin B12 compound/month such as a maximum of about 40 mcg/month, about 35 mcg/month, or about 30 mcg/month, for example, about 15-45 mcg/month, about 17.5-37.5 mcg/month, about 20-35 mcg/month, or about 20-30mcg/month.
  • Example: 1 Preparation of granules using Rapid Mixer Granulator
  • Drug solution was prepared by dissolving vitamin B 12 in sufficient quantity of water.
  • Lactose monohydrate was sifted through suitable sieve and loaded in rapid mixer granulator for dry mixing.
  • step 3 Drug solution of step 1 was added to lactose of step 2 in a rapid mixer granulator and the mixture was kneaded at slow speed of impeller and chopper.
  • step 3 Drug excipient mixture of step 3 was dried using rapid dryer at inlet temperature of 45°C for 45 minutes at airflow of 30.
  • step 5 Sifted dried material of step 4 was passed through a suitable sieve.
  • Step 6 granules were blended with magnesium stearate.
  • the blend of example 1 was compressed into tablet.
  • the drug release of tablets was determined by suitable dissolution apparatus.
  • Drug binder solution was prepared by dissolving vitamin B 12 in a sufficient quantity of water and Povidone was added to it, with stirring till it formed clear solution.
  • Lactose monohydrate was sifted through suitable sieve and loaded in the fluidized bed processor and warmed to solvent temperature.
  • Granules were prepared by spraying drug binder solution of step 1 on the lactose of step 2 in the fluidized bed processor, the entire process was carried out at 50 ⁇ 5 °C.
  • step 3 The granules of step 3 were dried in fluidized bed processor and the dried granules were sifted through sieve.
  • Step 5 granules were blended with magnesium stearate.
  • Drug binder solution was prepared by dissolving vitamin B12 in sufficient quantity of ethanol and Povidone was added to it with stirring till it forms clear solution.
  • Lactose monohydrate was sifted through suitable sieve and loaded in the fluidized bed processor.
  • Granules were prepared by spraying drug binder solution of step 1 on the lactose of step 2 in the fluidized bed processor, the entire process was carried out at 30 ⁇ 5 °C.
  • step 3 The granules of step 3 were dried in fluidized bed processor and the dried granules were sifted through sieve.
  • Step 5 granules were blended with magnesium stearate. 7) The pre-lubricated blend was compressed into tablet. Optionally, tablets were coated with coating solution.
  • composition Fl and F3 were evaluated to investigate the impact of formulation techniques on the content uniformity of vitamin B 12 in the respective compositions.
  • the vitamin B12 content uniformity was then determined along with assay, standard deviation and acceptance value.
  • Formulation Fl manufactured using rapid mixer granulator showed assay value of 56.2 %, indicating significant loss of API during product manufacturing.
  • Formulation F3 manufactured using top spray granulation showed assay value of 105.0 % (minimum 100.0%, Maximum 108.3%) with an acceptance value 9.78. This indicates that the drug loading is found to be uniform within plus/minus 5 % of the mean value.
  • the drug loading efficiency is high in the composition wherein top spray granulation was used in comparison the composition prepared by using rapid mixer granulator.

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

Abstract

L'invention concerne une composition pharmaceutique de vitamine B12 à faible dose avec un ou plusieurs excipients pharmaceutiquement acceptables et des procédés de fabrication de ladite composition. L'invention concerne une composition pharmaceutique orale solide de vitamine B12 à faible dose présentant une uniformité de teneur en vitamine B12 améliorée dans la composition.
PCT/IB2022/060539 2021-11-03 2022-11-02 Composition pharmaceutique de vitamine b12 à faible dose WO2023079445A1 (fr)

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IN202121050623 2021-11-03

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014152504A1 (fr) * 2013-03-14 2014-09-25 Pharmaceutical Productions Inc. Procédé de traitement de déficience en vitamine b12
US20190111059A1 (en) * 2017-10-17 2019-04-18 Marinus Pharmaceuticals, Inc. Compositions and methods for treating autism spectrum disorder
US10617700B1 (en) * 2016-02-26 2020-04-14 Michelle Ann Toothman Vitamin supplement compositions with enhanced bioavailability

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014152504A1 (fr) * 2013-03-14 2014-09-25 Pharmaceutical Productions Inc. Procédé de traitement de déficience en vitamine b12
US10617700B1 (en) * 2016-02-26 2020-04-14 Michelle Ann Toothman Vitamin supplement compositions with enhanced bioavailability
US20190111059A1 (en) * 2017-10-17 2019-04-18 Marinus Pharmaceuticals, Inc. Compositions and methods for treating autism spectrum disorder

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