DESC:
FIELD OF THE INVENTION
The present invention relates to 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.

BACKGROUND OF THE INVENTION
Vitamin B12 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 B12 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.

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 B12 is important for production of the DNA needed to make red blood cell. Deficiency of vitamin B12 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 varies 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 B12 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 B12.

WO 2021102053 discloses method of supplementing Vitamin B12 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 pre-processing 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 B12 and macromolecule carrier such as Gelucire to improve bioavailability and to improve the stability of vitamin B12.

All the referred applications cite various problems of handling methylcobalamin while making a suitable pharmaceutical dosage form. The prior art references fail to disclose pharmaceutical compositions of low dose vitamin B12 with an improved content uniformity of vitamin B12. Therefore, there is still a need for improving the content uniformity of vitamin B12 in the pharmaceutical composition of low dose 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 B12 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.

SUMMARY OF INVENTION
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. Surprisingly, the inventors found that 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). More preferably, the 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.

The invention is directed to a pharmaceutical composition of low dose of vitamin B12 i.e. lower than 5 mcg. Preferred, 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 B12 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, the pharmaceutical composition comprises vitamin B12 as an active not more than 1% of total weight of dosage form. In another aspect of the invention, the pharmaceutical composition comprises vitamin B12 and one or more pharmaceutically acceptable excipients in a ratio 0.004:99.996.

The pharmaceutical 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.

Other objects and advantages will become apparent from a review of the ensuing detailed description.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is described in detail by the way of reference only using the following definitions and examples. The present invention is not limited to methods, and experimental conditions described herein, as such methods and conditions may vary. The terminology used herein is, for the purpose of describing embodiments only, and is not intended to be limiting unless indicated, since the scope of the present invention will be limited only by the appended claims. All technical and scientific terms and phrases used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

DEFINITION
The term "comprising" is an open term. Therefore, the herein described pharmaceutical composition form may comprise more than one active pharmaceutical ingredients (APls). However, 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 B12” also known as methylcobalamin. Here, “low dose vitamin B12” 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.

The term "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). In one embodiment, 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). When controlling the quality of e.g. capsules or tablets, 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. In the context of the present invention, assay content, RSD and AV are preferably calculated as set out in "The United States pharmacopeia", 37th revision, physical tests, Uniformity of Dosage Units. The term "content uniformity of vitamin B12" 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. In one of embodiment, 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.

The term “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. Using fluidized bed processors, 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.

The term “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.

The term “spray drying” as used herein is also a well-known technique in the art that is also used for the preparation of drug/excipient premix. In this process 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.

The term “excipient” as used herein 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.

The term “solvent” as used herein refers to any aqueous or non-aqueous liquid material where it used to dissolve or disperse active ingredient partially or completely. Non-limiting examples of such solvents are an aqueous solvent such as water or aqueous buffer and non-aqueous solvent such as ethanol, propylene glycol.

The term “binder” as used herein include starch, gelatin, natural sugars such as glucose or beta-lactose, corn 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. In most preferred embodiment, binder is povidone. Binder is present in concertation range 1-15% w/w of total composition, preferably 5-5%.

The term “diluent” or “filler” as used herein 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. In preferred embodiment of invention diluent is lactose monohydrate.

The term “glidant” and “lubricant” as used herein include as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol.

The term “disintegrant” as used herein include, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, methyl-cellulose, agar, bentonite, xanthan gum and the like.

In one of embodiments of present invention, pharmaceutical composition comprises Vitamin B12 as an active not more than 1% of total weight of composition. Further, in present invention, Vitamin B12 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.

In an embodiment, 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 B12 and methods of making such composition with an improved content uniformity of vitamin B12 in the composition.

In another embodiment, 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.

In another embodiment invention provides 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.

In another aspect, 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.

In another aspect, 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.

In another embodiment, the invention provides a solid oral pharmaceutical composition of vitamin B12, wherein the amount of vitamin B12 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.

In another embodiment 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 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.

In another embodiment 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 top spray granulation and the amount of vitamin B12 in the composition is 0.004% w/w of the total composition.

In another embodiment 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 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.

In another embodiment 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.

In another embodiment 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 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.

In another embodiment 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 spray drying and the amount of vitamin B12 in the composition is 0.004% w/w of the total composition.

In one of the embodiments, 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.

Example: 1: Preparation of granules using Rapid Mixer Granulator

Sr. No. Ingredient (F1) Quantity/Unit (mg)
Intragranular
1 Methylcobalamin 0.0024
2 Lactose Monohydrate 34.9976
3 Purified Water q.s.
Extragranular
4 Lactose Monohydrate 6.0000
5 Microcrystalline Cellulose 12.7000
6 Croscarmellose Sodium 6.0000
7 Magnesium Stearate 0.3000
Total weight 60.0000

1) Drug solution was prepared by dissolving vitamin B12 in sufficient quantity of water.
2) Lactose monohydrate was sifted through suitable sieve and loaded in rapid mixer granulator for dry mixing.
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.
4) Drug excipient mixture of step 3 was dried using rapid dryer at inlet temperature of 45°C for 45 minutes at airflow of 30.
5) Sifted dried material of step 4 was passed through a suitable sieve.
6) Extra-granular lactose, microcrystalline cellulose and croscarmellose sodium were sifted through a sieve and mixed and blended with granules of step 5.
7) Step 6 granules were blended with magnesium stearate.

Example: 2: Preparation of tablet using Rapid Mixer Granulator
The blend of example 1 was compressed into tablet. The drug release of tablets was determined by suitable dissolution apparatus.

Example 3: Preparation of tablet using Top Spray Granulator

Sr. No. Ingredient (F2) Quantity/Unit (mg)
Intragranular
1 Methylcobalamin 0.0024
2 Lactose Anhydrous 43.6976
3 Povidone 2.0000
4 Purified Water q.s.
Extragranular
5 Lactose Anhydrous 11.0000
6 Croscarmellose Sodium 3.0000
7 Magnesium Stearate 0.3000
Core Tablet Total 60.0000
8 Opadry Yellow 03B52205 1.8000
Coated Tablet Total 61.8000

1) Drug binder solution was prepared by dissolving vitamin B12 in a sufficient quantity of water and Povidone was added to it, with stirring till it formed clear solution.
2) Lactose monohydrate was sifted through suitable sieve and loaded in the fluidized bed processor and warmed to solvent temperature.
3) 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 ºC.
4) The granules of step 3 were dried in fluidized bed processor and the dried granules were sifted through sieve.
5) Extra-granular lactose and croscarmellose sodium were sifted through a sieve and mixed and blended with granules of step 4.
6) Step 5 granules were blended with magnesium stearate.
7) The pre-lubricated blend was compressed into tablet. Optionally, tablets were coated with a coating solution.

Example 4: Preparation of tablet using Top Spray Granulator

Sr. No. Ingredient (F3) Quantity/Unit (mg)
Intragranular
1 Methylcobalamin 0.0024
2 Lactose Anhydrous 43.6976
3 Povidone 3.0000
4 Ethanol q.s.
Extragranular
5 Lactose Anhydrous 10.0000
6 Croscarmellose Sodium 3.0000
7 Magnesium Stearate 0.3000
Core Tablet Total 60.0000
8 Opadry Yellow 03B52205 1.8000
Coated Tablet Total 61.8000

1) 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.
2) Lactose monohydrate was sifted through suitable sieve and loaded in the fluidized bed processor.
3) 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 ºC.
4) The granules of step 3 were dried in fluidized bed processor and the dried granules were sifted through sieve.
5) Extra-granular lactose and croscarmellose sodium were sifted through a sieve and mixed and blended with granules of step 4.
6) Step 5 granules were blended with magnesium stearate.
7) The pre-lubricated blend was compressed into tablet. Optionally, tablets were coated with coating solution.

The composition F1 and F3 were evaluated to investigate the impact of formulation techniques on the content uniformity of vitamin B12 in the respective compositions. The vitamin B12 content uniformity was then determined along with assay, standard deviation and acceptance value.

Formulation F1 manufactured using rapid mixer granulator showed assay value of 56.2 %, indicating significant loss of API during product manufacturing. The 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.
,CLAIMS:
1. A solid oral pharmaceutical composition comprising vitamin B12 and one or more suitable pharmaceutically acceptable excipients, wherein dose of vitamin B12 is less than 5 microgram.

2. The pharmaceutical composition of claim 2, wherein the pharmaceutical acceptable excipient is selected from diluent, filler, binder, disintegrant, lubricant, carrier, coating agent, acidity regulators or combination thereof.

3. The pharmaceutical composition of claim 1, wherein the composition is prepared by a process that includes top spray granulation.

4. The pharmaceutical composition of claim 1, wherein the composition is prepared by a process that includes solvent evaporation.

5. The pharmaceutical composition of claim 1, wherein the composition is prepared by a process that includes spray drying.

6. The pharmaceutical composition of claim 1, wherein the composition is administered alone or as a fixed dose combination with other therapeutic agents.