A NOVEL PROCESS INVOLVING A DRUG DELIVERY SYSTEM IN INJECTIBLE FORM IN RESPECT OF METHYLCOBALAMIN / MECOBALAMIN
This invention pertains to pharmaceutical industry. It is concerned with a novel process involving a drug delivery system in an injectible form in respect of methylcobalamin, which is commonly termed as Vitamin B-12 with a methyl compound in the place of the cyano compound. More particularly this invention pertains to a novel process involving manufacture of a drug delivery system by way of injectible form. The application of the various pharmaceutical compositions of melthycobalamin in injectable form leads to very important advantages which will be enumerated in the following description.
It is a well known fact that a pharmaceutical formulation, if taken in a tablet form, does not get absorbed in to the system fully and effectively. Similar is the situation in case of methylcobalamin formulation in the tablet form. When a methylcobalamin formulation is taken in the form of tablets the absorption of full doze of the medicine in the blood stream is not complete, as there is a possibility that a certain percentage of the doze will be excreted and it does not get absorbed in the system. In order to overcome this difficulty of lack of full absorption in to the system it is envisaged to administrate the medicine or formulation using a novel process for the manufacture of drug in the form of injection.
The uniqueness and novelty in the process involved in the manufacture of Methylcobalamin in injectible form lies in the fact that the Applicant is confident that no other person in India has perfected the said process. The said process could not be perfected due to the fact that the composition has to be so perfect so that no sedimentation and cloudiness of the drug arises and at the same time shelf life and the potency of the drug is maintained at the guaranteed level on its administration.

At the outset the description which follows should be understood that it only illustrates a particular form of this invention. However, such particular form is only an exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is to be understood as an exemplary embodiment and reading of the invention is not intended to be taken restrictively.
The description outlines rather broadly, preferred and alternative features of the present invention so that those skilled in the art may better understand the detailed description of the invention that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed conception and specific embodiment as a basis for designing and modifying other structures for carrying on the same purposes of the present invention. Those skilled in the art should realize such equivalent conception does not depart from the spirit and scope of the invention in its broadest form.
The accompanying description is intended to provide further understanding of the invention and is incorporated in and constitute a part of invention. The examples illustrate an embodiment of invention and together with the-description illustrative principle of invention. The examples should not be taken as implying any necessary limitation on the essential scope of invention.
The invention has been explained in relation to specific embodiment. It is inferred that the foregoing description is only illustrative of the present invention and it is not intended that the invention be limited or restrictive thereto. Many other specific embodiments of the present invention will be apparent to one skilled in the art from the foregoing disclosure. All substitutions, alterations and modification of the present invention which come within the scope of the following claims to which the present invention is readily susceptible without departing from the spirit of the invention do form part of the invention itself.

The object is to invent a novel process for the formulations having methylcobalamin as basic material and application of this said composition by way of drug delivery system in the form of injection.
The another objective of invention is to invent a correct technique of administration of methylcobalmin in to the human body so that the drug is completely absorbed in the system.
Further objects of invention will be clear from the following description.
Now the invention is described in detail in the following description. The nature of the invention and the manner in which the invention is to be performed has been clearly described in the complete specification.
The invention is described in detail with reference to examples given in the complete specification. The feature and advantages of the invention as summmarised in the claims will be understood more clearly from the following description with reference to accompanying examples.
Examples show a possible embodiment of invention given by way of non limiting example.
Master formula record will have the following particulars regarding the invented composition.

MASTER FORMULA RECORD METHYLCOBALAMIN INJECTION 500 meg , ml -1 ml

Formula
Each ml contains-Methylcobalamin 500 meg Benzyl Alcohol IP 2% DISODIUMEDTA:0.1% Mannitol LP, Pyrogen fr.ee 50 mg.
Pack Size
1ml solution in 1ml amber ceramic printed in imported tubing. Each ampule will be packed in blister. Each blister in a printed Monocarton along with literature--and disposable syringe 10 such cartons will be packed in an inner box with box label. 10 such boxes will be packed in a Shipper.
Storage
Store in a cold place, Protect from Light.
It is to be noted the composition of the Methylcobalamin in the invention is in the following proportions
(i) Methylcobalamin 500 mcg
(ii) Methylcobalamin 1000 mcg
(iii) Methylcobalamin 1500 mcg
(iv) Methylcobalamin 2500 mcg

Batch Size 100 litres

Precautions to be taken during manufacture are as follows-
• Carry out manufacturing and filling operations under filtered Nitrogen cover
• Check cleanliness of the area, vessels, equipments etc. to make sure that they
are sterile.
• Use only freshly collected water for Injection IP and only after QC approval.
Water should be cooled to 2-8 Degree centigrade before manufacturing.
• Wear nose masks, gloves and protective clothing during manufacture and filling operations.
• Check the weights of all ingredients before adding to the bulk.
• Follow GMP guidelines.

special Precautionary Measures are as follows
• Protect from undue exposure to light throughout the process
• Take utmost precaution during sampling, dispensing, manufacturing, filling, inspection and packing in order to avoid exposure to any kind of light.
• Use red light wherever possible.
• After each process put the finished or semi finished product in to a light resistant container.
• During manufacture of the solution and its storage from the sterile filtration process onwards, particular care must be taken to avoid cross contamination with micro organisms or other foreign particles.
• The solution must undergo sterile filtration by being passed through sterile filters.
• Gassing with Nitrogen is essential during the manufacture and filtration operation.
• It must be filtered into sterile containers and the solution must be filled into sterile ampoules while ensuring the greatest possible exclusion of microorganisms and other foreign particles.
List of equipments used for preparation of the composition.
(a) SS - 316 vessel of capacity 200 litre with stirring capacity (JACKETED)
(b) Jet Washing ampoule Machine
(c) Dry Heat Sterlizer
(d) Autoclave
(e) Ampoule filling and sealing Machine
(f) Inspection Cabinets
(g) Laminar Air Plow
(h) Flow Meters & Regulators
(0 Blister Packing Machine


1. Filtration
After QC approval filter the solution with protection from light under Nitrogen pressure through a sterilized membrane filter (Millipore model) and pre-filter (Sartorius model). Collect the filtered solution in sterile containers that part to be gassed with Nitrogen throughout the filtration process, Use Silicon tubings.
• Filling
Taking apropriate antimicrobial precautions, fill the solution immediately into washed and sterilized ampoules. Send test request to QC to Collect sample for analysis.

• Leak testing
Leak test the ampoules for any breakage or any hair line cracks. Record the quantity rejected.
• Visual Inspection
After QC release examine the ampoules for Faulty filling, Colour & clarity of the solution, foreign particles,
« Sealing
Quantities of Packing Components required for packing 100 litres of solution.


Packing
• Overprint Carton with proper printed matter and check for compliance of printed matter on all packaging components. Obtain QC approval.
• Check cleanliness of packaging area before start of operation.
• Label visual inspection passed ampoules and pack each ampoule in a carton with disposable syringe and a literature.
• Check the weight of FBC and record the same.
• Transfer the packed stock after QC clearance to the bonded ware house through a Finished Goods Transfer Note.
• Carry out reconciliation of all packing materials used and record the same in the manufacturing record.
• Return the excess packing materials to stores through a material return note. Destroy the rejected packing materials and record the same.
• Check yield limits after packing and if found to be out of limits investigate the cause and record the same in the manufacturing record. (Packed Yields 92 to 96% based on the theoretical fill volume 1.1ml).
QC / QA Checks
QC/QA will carry out chemical analysis of all raw materials, in process samples and finished products for compliance to specification laid down for the product as per the standard analytical procedure available in the laboratory.
QC/QA will check all packing components for compliance to specifications and QC approved ones will be issued for production.
During filling and packing of the batch the QC/QA personnel will carry out in process checks and record the observations.
The packed stock will be transferred to the bonded warehouse through a Finished Goods Transfer Note after QC/QA has inspected the stock.

The batch will be released for sale only after QC/QA reviews the Batch Manufacturing Record for compliance to all processing requirements.
Now the process of manufacturing the invented composition is given in the form of flow chart. Various sequence of steps involved are illustrated in the first diagram of flow chart which accompany the complete specification.
In the flow diagram shown in figure 2 of the drawings essential details of entire process is fully illustrated.
A solution preparation has various steps and critical parameters of process are illustrated in figure 1.
Fig.2 of the drawings shows the entire process according to invention. In figure 2 preparation of solution is shown in the right side of flow diagram. If uses purified water prepared has shown in the middle potion of flow diagram. The purified water is also used in cleaning and purification / sterilization of ampule and shown in the left side of figure (2).
The entire process is carried out under extremely clean and at a temperature conducive for quality product. This is a critical aspect of the invention. The critical conditions and parameters are illustrated in the figure (2) of drawings.
Subsequent to the flow diagram explaining various steps and precautions to be taken in the preparation of the composition according to invention, the invention is further illustrated by way of examples to explain various aspects of invention. The features and advantages have been summarised in the claims will be understood more easily from the following description with reference to following examples each of which, shows possible embodiment of the invention given by way of non-limitive example.

Examples
The following examples provided to give a more detailed understanding of invention, the particular amount, compositions and parameters are meant to be exemplary and not indenting to specifically limit the scope of the invention.
MECOBALAMIN INJECTION 500 meg / m 1 - 1 ml



DISODIUMEDTA 0.100
Precaution- While weighing Mecobalamin care should be taken to avoid contact with light, Dispensing should be done under red light.
Name of weighing balance used: Metier 200 Gm Capacity / Essae Taroka 30 kg Capacity


Equipment's calibrated calibrated by
pH meter calibrated calibrated by
Caution - Manufacturing should be done under red light only. Utmost care should be taken to minimise light exposure over the solution.



Strip Chart / Indicator Checked
Filtration: Filtration carried as per SOP No. P - 017
Equipment Used 293 mm Membrane Holder Make-" Pharmalab
Prefilter Used: Final Filter Used:

AMPOULE FILLING LINE CLEARENCE

VISUM, INSPECTION:
Should be done under red light only. Utmost care should be taken to minimise the exposure to light as per SOP No.



Quantity of Cartons/Labels Rejected
Rejected Quantity Destroyed By
Printed Materials Given to Packing Department by: Authorised By:
Received by Packing Department:

Packing In process Checks

Description : Dark red crystalline powder
Solubility ** Soluble in water
Identification (A) To 1 mg of methylcobalamin sample add 0.05g of potassium sulphate heat until it melts. Crush the material with glass rod then add 3 ml of water, boil to dissolve. Add 3 drops of phenolphthalein indicator and add dilute sodium hydroxide until it shows a pink colour. To this solution add 0.5 g of sodium acetate, 0.5 ml of dil. Acetic acid and 0.5 ml of l-nitroso "2" naphthol-3,6 disulfonic sodium solution (0.2% solution in water). The resulting solution should show red to salmon pink colour. To this add 0.5 ml of Hcl boil for 1 minute. The red colour should not disappear. (B) Bv Spectrophotometer.The light absorption in the range of 230 - 600 nmof 0.0030% w/v solution exhibit three maxima at about 266, 346 & 522nm. The ratio of the absorbance at about 346 nm to that at about 522 nm is 0.35 to 0.55 and the ratio of the absorbance at about 346 nm to that at about 266 nm is 1.1 1.30. Acidity: pH of 0.2% w/v solution is between 6 and 8Loss on drying: Not more than 12% determined on 0.05g of sample under 5mm Hg phosphorous pentoxide at 100oc for 3 Hours.
Location: Quality control

AssayStandard Preparation:
Weigh accurately about 20 mg of vitamin B12 standard in 100 ml volumetric flask add water. Dissolver and make up to the volume with water (Standard stock solution)
Pipette out 5 ml of standard stock solution in 50 ml volumetric flask and add potassium cyanide solution (0.5% solution in water) and make up to the volume with same solution. •
Sample preparationWeigh accurately about 20 mg of methylcobalamin sample in 100ml volumetric flask and water dissolve and make up the volume with water. (Sample stock solution).

Pipette out 5 ml of sample stock solution in 50 ml volumetric flask and add potassium cyanide solution (0.5% solution in water) and make up the volume with same solution.
Shake both sample and standard solution and keep at a distance at about 30 cm from yellow light lamp for 90 minutes in radiation. Measure the absorbance of standard and sample solution using potassium cyanide solutionO.5% W/v solution in water) as blank at wavelength 368 nm.
Calculation"Abs of sample x Wt. of Std/dilutionx100 ,
Abs of standard x Wt. of Sam / Dilution On aried basis = as such assay x 100
100Bacterial Eddotoxin test. Not more than 400 EU/mg)Storage conditionProtected from light at a temperature of 2° to 8° cThe contents of the opened container should be usedimmediately.

ChallanNo. &Date Quantity Received Date of Receipt Date of Sampling Quantity Sampled Date of Analysis Mfg Date Date BatchNo,
711/ 30.04.02 250.0 gm 02/05/02 15/05/02 200 mg 17/05/02 04/02 3/06 A-020295/00 7898--

1. Description
2. Solubility
3. Identification
4. pH
5. Loss on Drying
6. Assay as such basis
7. On dried basis
8. Bacterial endotoxin test

A dark red crystalline powder
Complies with in house specification
Complies with in house speciJ5.cation
6.96 (Limit 6.0 to 8.0)
4.31% (Limit 6.0 to 8.0)
95.77%
100.07% (limite NLT 97%)
Complies test (Lt 400 EU /mg)

Remarks: The sample complies with the Standards of Quality as prescribed in in-house specification.

Location • Quality Control
Description ' A dark red coloured clear solution
pH : 6.0 to 8.0
Volume • Average volume NMT 1.1 ml (labeled volume 1ml)
Identification:
Take equivalent to 1 mg of methylcobalamin add 0.05 g of potassium sulphate, heat until it melts crush the material with a glass rod, then add 3 ml water, boil to dissolve, add 3 dips of phenolphthalein indicator and add dilute sodium hydroxide solution until it shows a pink colour. To this solution add 0.5 g of sodium acetate, 0.5 ml of dilute acetic acid and 01 of 1 nitrose-2- naphthol" 3, 6* disulfonic sodium solution. (0.2% solution in water). The resulting solution should show red to salmon pink colour. To this add 0.5 ml of Hydrochloric acid boil for one minute, the red colour should not disappear.
Assay:
Standard Preparation:
Weigh accurately about 20 mg of cyanocobalamin R.S. in 100ml volumetric flask, add water, dissolve and make up to the volume with water (Standard stock-' solution) Pipette out 5ml of standard stock solution in 50 ml of volumetric flask and add potassium cyanide solution (0.5% W/v solution in water) and make up to the volume with same solution.
Location: Quality Control
Assay
SAMPLE PREPARATION:
Volume of sample taken is 2 ml (equivalent to 1000 meg) in 50 ml of volumetric flask and add potassium cyanide solution (0.5% w/v solution in water) and make up the volume with same solution. Measure the absorbency of standard and

sample solution using potassium cyanide solution as blank at wavelength 368 nm after 90 minutes.

METHOD OF ANALYSIS
Microbiological assay of Methylcobalamin injection Claim: Each ml contains Methylcobalamin 500mcg Actual input: 650mcg/ ml (30% Overage)
Aim: To determine the content of Methylcobalamin.
Method: Cup plate method two level fractional assay
Materials required:
1. Petriplates (90mm dia) 5No's
2. B12 Assay agar (Himedia coad No: MllO)
3. B12 Culture agar (Himedia coad No: M 185)

4. Casein Hydrolysate broth (Himedia Coad No: M200A)
5. Water for injection bulk
6. Cork borer (8.0 mm diameter)
All above materials are sterilized by autoclave at 15Lbs (l21oC) pressure for 20 minutes.
Media preparation:
Suspend 5.15gms in 100 ml of distilled water; boil to dissolve the medium completely. Sterilize by autoclaving at 15Lbs pressure (l21oC) for 15 minutes.

Inoculam preparation:
Organism used: Escherichia Coli mutant NCIM 2068
Inoculate an loop full of culture from working culture slant (B12 Culture agar) in 100 ml of Casein hydrolysate broth, incubate in 37oC for 24 hours and kept it in 2 to 8oC for up to 7 days.
Assay agar plate preparation:
Cool 100 ml of sterilized assay agar medium to about 45°C and add 1 ml of inoculam, mix well and dispense accurately 20 ml to each sterile petri plates and allow it to solidify.

SI and S2 are refereed to as Standard high and standard low concentration
respectively
Ul and U2 are refereed to as Sample high and Sample low concentration
respectively.
Procedure-Cut four well on the agar surface with 8.00mm diameter cork borer. Then add sufficient quantity (60ml) of standard and sample dilution to the respective well and allow it to diffuse for half an hour. Incubate the plates at 37oC for not less than 18 hours.

Calculation-

Results of in house testing of various combinations of the products for which patent protection is claimed are listed below.

CERTIFICATE OF ANALYSIS
Example -1

Example - 4
Name of the product •
Storage Condition : 20 to 23 Deg At 60% RH± 5%

Example - 5 Name of the Product:

Conclusion ' In the 25 minutes the sample complies the above said as per specification.

Example - 6
Name of the Product -

Conclusion • In the 30 minutes the sample complies the above said as per specification
ExEimple — 7 Name of the Product'

Conclusion - In the 35 minutes the sample complies the above said as per specification

Example - 8
Name of the Product •

Conclusion^ Before filling the sample comphes the above said test as per
specification. ^
Example - 9 Name of the Product •

Conclusion- The sample complies the above said test as per specification

Example - 10 Name of the Product -
1. Name of the product • Bicobal inj-lml
2. Condition '• Visual inspection process.

Conclusion: The sample complies the above said test as per specification.
Example-11
Name of the Product:


Example -12 Name of the Product:


CERTIFICATE OF ANALYSIS
QUALITY ASSURANCE
TESTS OBSERVATIONS LIMITS
Description Dark red crystalline Dark red crystalline
Identification powder powder
Loss on drying Complies To comply to the test
Assay 4.50% Not more than 12%
96.78% Not less than 95%
REMARKS : THE MATERIAL COMPLIES TO THE SPECIFICATIONS
CERTIFICATE OF ANALYSIS
QUALITY ASSURANCE
TESTS OBSERVATIONS LIMITS
Description Dark red crystalline Dark red crystalline
Identification powder powder
Loss on drying Complies To comply to the test
Assay 4.50% Not more than 12%
Total Viable count 96.78% Not less than 95%
Total Enterobacteriaceae 1800 cfu/g Not more than 50,000 cfu/gNot more than 30 cfu/gNot more than 100 cfu/gAbsent by test
Yeast & Mould count Pathogens Bacterial Endotoxin <10 cfu/g 30 cfu/g AbsentComplies
Not more than 400 EU/mg
REMARKS: THE MATERIAL COMPLIES TO THE SPECIFICATIONS

PRODUCT DEVELOPMENT
Example -1
Methylcobalamin Injection 1ml.
1000mcg For IM/IV use only
Composition:
Each ml contains :
Methylcobalamin 1000mcg
Benzyl Alcohol I.P/SS 2% w/v
(as preservative)
Water for Injection LP. q.s.
Methylcobalamin:
D Methylcobalamin is a Neurotropic and acts as a growth promoter for nerve cells,
a property which helps to regenerate Central and Peripheral nervous tissue
damaged in disorder such as diabetic peripheral neuropathy, D Methylcobalamin acts as a methyl donor for the synthesis of lecithin, a major
component of the Myelin sheath. D Methylcobalamin facilitates methylation of t-RNA which plays a fundamental
role in protein synthesis and stimulates methionine synthesis and helps to
restore normal levels of RNA in nerve cells, D Methylcobalamin acts as a co-factor in the enzyme methionine synthase which
regnerates methionine, thus generating an increased supply of S-Adenosyl
Methionine (SAMe) and SAMe protects from Neurotoxicity. D Methylcobalamin Normalizes Nerve cell conduction by healing the damaged
nerve cells and restores delayed synaptic transmission and diminished
neurotrasmitters to normal. D Methylcobalamin improves the excitabihty of the nerve fibres and thus improve
the neurotransmission.
INDICATIONS:
I. Diabetic Neuropathy
II. Other Neuropathies

a) Drug Induced / Alcohohc Neuropathy
b) Optic Neuritis
c) Muscular Dystrophy
d) Neuralgia

Dosage • As directed by the Physician.
Storage • Store in a cool, dry place and Protected from light.
Warming: Not to be used in New born or Premature Infants.
Example - 2 Mecobalamin Injection 1 ml
DESCRIPTION:
Mecobalamin is one of the two active coenzyme forms of vitamin B12 (the other being adenosylcobalamin). It is co-factor in the enzyme methionine synthase which functions to transfer methyl groups for the regeneration of methionine from homocysteine. Mecobalamin is closely involved in folate metaboUsm which is pivotal for the synthesis of purines and pyrimidines and therefore of deoxyribonucleic acid (DNA). Mecobalamin also acts as a methyl donor for the synthesis of lecithin, a major component of the myelin sheath.
COMPOSITION:
Each ampoule contains 500 meg of Mecobalamin in 1ml of the solvent.
PHAEMACOLOGY:
1. Mecobalamin is a kind of endogenous coenzyme B12. Mecobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.
2. Mecobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis. Mecobalamin is better transported to nerve cell organelles than cyanocobalamin in animals. It has been shown in experiments with cells from the brain origin and spinal nerve cells in mice to be involved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utilization and metabohsm of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in animals more than cobamamide does.
3. Mecobalamin promotes axonal transport and axonal regeneration. Mecobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from animals models with streptozotocin induced diabetes mellitus. It exhibits neuropathologically and electro physiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine models of axonal degeneration in mice and neuropathies in animals with spontaneous diabetes melhtus.

4. Mecobalamin promotes myelination (Phospholipid synthesis). Mecobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipid and increases myelination of neurons in animals tissue culture more than cobamamide does.
5. Mecobalamin restores delayed synaptic transmission and diminished neurotransmitteres to normal. Mecobalamin, restores end-plate potential induction early by increaing nerve fiber excitabihty in the crushed sciatic nerve. In addition, Mecobalamin normalizes diminished brain tissue levels of acetylcholine in animals fed a choline deficient diet.
6. Mecobalamin promotes the maturation and division of erythroblasts, thereby alleviating anemia. It is well known that vitamin B12 deficiency may cause specific megaloblastic anemia. Mecobalamin promotes nucleic acid synthesis in bone marrow increasing erythrocyte production and promotes the maturation and division of erythroblasts, thereby increasing erythrocyte production Mecobalamin brings about a rapid recovery of diminished red blood cell, hemoglobin, and hematocrit in vitamin B12 deficient animals.
INDICATIONS:
a) Peripheral neuropathies: Diabetic Neuropathy, alcoholic Neuropathy, Drug induced Neuropathy.
b) Dementia of Alzheimer's type.
c) Trigeminal & occipital neuralgia
d) Parkinson's disease
e) Bells palsy
0 Megaloblastic anaemia caused by vitamin B12 deficiency.
g) Cancer, Male impotence, Hyperhomocystinemia & Sleep disturbances.
DOSAGE:
Peripheral Neuropathy: The usual dosage for adults is 1 ampoule (SOOmcg of Mecobalamin) daily by IM or IV 3 times in a week. The dose may be adjusted depending upon the patients age & symptoms.
Megaloblastic Anaemia:
The usual dosage for adults is 1 ampoule (500mcg of Mecobalamin) daily by IM or IV 3 times in a week. After 2 months the dose should be reduced to a single administration of 1 amp. At 1-3 months interval for maintenance therapy.
Other Indications: As directed by the physician.

PRECAUTIONS:
1. Adverse Reactions : Adverse reactions were reported in 13 of 2872 patients (0.45%). (At the end of the reexamination period) Clinically significant adverse reactions (incidence unknown)
Anaphylactoid reaction : Anaphylactoid reaction such as decrease in blood pressure or dyspnea, may occur. Patients should be carefully observed. In the event of such symptoms, treatment should be discontinued immediately and appropriate measures taken.
STORAGE:
Store in a cold place protect from light.
PRESENTATION:
1x1 Amp. With disposable syringe.
Example - 3 Mecobalamin 500mcg/1m1Amp.
The Neurologically active form of Vitamin B12

DESCRIPTION:
Mecobalamin is one of the two active coenzyme forms of vitamin B12 (the other being adenosylcobalamin). It is a co-factor in the enzyme methionine synthase which functions to transfer methyl groups for the regneration of methionine from homocysteine. Mecobalamin is closely involved in folate metabolism which is pivotal for the synthesis of purines and pyrimidines and therefore of deoxyribonucleic acid (DNA). Mecobalamin also acts as a methyl donor for the synthesis of lecithin, a major component of the myelin sheath.
COMPOSITON: Each Ampoule contains 500mcg of Mecobalamin in 1ml of the solvent. PHARMACOLOGY:
1. Mecobalamin is a kind of endogenous coenzyme B12. Mecobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.

2. Mecobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis. Mecobalamin is better transported to nerve cell organelles than cyanocobalamin in animals. It has been shown in experiments with cells from the brain origin and spinal nerve cells in mice to beinvolved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utilization and metabolism of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in animals more than cobamamide does.
3. Mecobalamin promotes axonal transport and axonal regeneration. Mecobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from animals models with streptozotocin induced diabetes mellitus. It exhibits neuropathologically and electro physiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine models of axonal degeneration in mice and neuropathies in animals with spontaneous diabetes mellitus.
4. Mecobalamin promotes myelination (Phospholipid synthesis). Mecobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipid and increases myelination of neurons in animals tissue culture more than cobamamide does.
5. Mecobalamin restores delayedsynaptic transmission and diminished neurotransmitteres to normal. Mecobalamin, restores end-plate potential induction early by increaing nerve fiber excitability in the crushed sciatic nerve. In addition, Mecobalamin normalizes diminished brain tissue levels of acetylcholine in animals fed a cholinedeficient diet.
6. Mecobalamin promotes the maturation and division of erythroblasts, thereby alleviating anemia. It is well known that vitamin B12 deficiency may cause specific megaloblastic anemia. Mecobalamin promotes nucleic acid synthesis in bone marrow increasing erythrocyte production and promotes the maturation and division of er3rthroblasts, thereby increasing erythrocyte production Mecobalamin brings about a rapid recovery of diminished red blood cell, hemoglobin, and hematocrit in vitamin B12 deficient animals.
INDICATIONS : Peripheral Neuropathies : Dementia, Peripheral neuropathy, alcoholic Neuropathy, Drug induced Neuropathy, Trigeminal & Occipital Neuralgia, Parkinson's disease.
Bells Palsy : Megaloblastic anaemia caused by vitamin B12 deficiency Cancer, Male impotence, Hyperhomocystinemia & Sleep Disturbances.

DOSAGE : Peripheral Neuropathy : The usual dosage for adults is 1 ampoule (500mcg of Mecobalamin) daily by IM or IV 3 times in a week. The dose may be adjusted depending upon the patients age & symptoms.
Megaloblastic Anaemia :
The usual dosage for adults is 1 ampoule (500mcg f Mecobalamin) daily by IM or IV 3 times in a week. After 2 months the dose should be reduced to a single administration of 1 amp. At 1-3 months interval for maintenance therapy.
Other Indications' As directed by the physician.
PRECAUTIONS :
1. Adverse Reactions - Adverse reactions were reported in 13 of 2872 patients (0.45%).
(At the end of the reexamination period) (1) Clinically significant adverse reactions (incidence unknown)
Anaphylactoid reaction : Anaphylactoid reaction such as decrease in blood pressure or dyspnea, may occur. Patients should be carefully observed. In the event of such symptoms, treatment should be discontinued immediately and appropriate measures taken,
STORAGE: Store it in a cold, dry place protect fi:om light and moisture.
PRESENTATION : 1x1 Amp. With disposable syringe.
Example - 4 Methylcobalamin 500mcg / 1ml Amp.
The Neurologically active form of Vitamin B12
DESCRIPTION:
Methylcobalamin is one of the two active coenzyme forms of vitamin B12 (the other being adenosylcobalamin). It is a co-factor in the enzyme methionine synthase which functions to transfer methyl groups for the regenration of methionine from homocysteine. Methylcobalamin is closely involved in folate metabolism which is pivotal for the synthesis of purines and pyrimidines and therefore of deoxyribonucleic acid (DNA). Methylcobalamin also acts as a methyldonor for the synthesis of lecithin, a major component of the myelin sheath.
COMPOSITION : Each Ampoule contains 500mcg of Methylcobalamin in 1ml of the solvent.

PHARMACOLOGY:
1. Methylcobalamin is a kind of endogenous coenzyme B12. Methylcobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.
2. Methylcobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis. Methylcobalamin is better transported to nerve cell organelles than cyanocobalamin in animals. It has been shown in experiments with cells from the brain origin and spinal nerve cells in mice to beinvolved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utilization and metabohsm of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in animals more than cobamamide does.
3. Methylcobalamin promotes axonal transport and axonal regeneration. Methylcobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from animals models with streptozotocin induced diabetes mellitus. It exhibits neuropathologically and electro physiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and . vincristine models of axonal degeneration in mice and neuropathies in animals with spontaneous diabetes mellitus.
4. Methylcobalamin promotes myelination (Phospholipid synthesis). Methylcobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipid and increases myelination of neurons in animals tissue culture more than cobamamide does.
5. Methylcobalamin restores delayedsynaptic transmission and diminished neurotransmitteres to normal. Methylcobalamin, restores end-plate potential induction early by increaing nerve fiber excitability in the crushed sciatic nerve. In addition, Methylcobalamin normalizes diminished brain tissue levels of acetylcholine in animals fed a cholinedeficient diet.
6. Methylcobalamin promotes the maturation and division of erythroblasts, thereby alleviating anemia. It is well known that vitamin B12 deficiency may cause specific megaloblastic anemia, Methylcobalamin promotes nucleic acid synthesis in bone marrow increasing erythrocyte production and promotes the maturation and division of erythroblasts, thereby increasing erythrocyte production Methylcobalamin brings about a rapid recovery of diminished red blood cell, hemoglobin, and hematocrit in vitamin B12 deficient animals.

INDICATIONS : Peripheral Neuropathies : Dementia, Peripheral neuropathy, alcohohc Neuropathy, Drug induced Neuropathy, Trigeminal & Occipital Neuralgia, Parkinson's disease.
Bells Palsy - Megaloblastic anaemia caused by vitamin B12 deficiency - Cancer, Male impotence, Hyperhomocystinemia & Sleep Disturbances.
DOSAGE ' Peripheral Neuropathy : The usual dosage for adults is 1 ampoule (500mcg of Methylcobalamin) daily by IM or IV 3 times in a week. The dose may be adjusted depending upon the patients age & symptoms.
Megaloblastic Anaemia •
The usual dosage for adults is I ampoule (500mcg of Methylcobalamin) daily by IM or IV 3 times in a week. After 2 months the dose should be reduced to a single administration of 1 amp. At 1-3 months interval for maintenance therapy.
Other Indications' As directed by the physician.
PRECAUTIONS : 1. Adverse Reactions : Adverse reactions were reported in 13 of 2872
patients (0.45%). (At the end of the reexamination period)
(l) Clinically significant adverse reactions (incidence unknown)
Anaphylactoid reaction • Anaphylactoid reaction such as decrease in blood pressure or dyspnea, may occur. Patients should be carefully observed. In the event of such symptoms, treatment should be discontinued immediately and appropriate measures taken.
STORAGE: Store it in a cold, dry place protect from light and moisture.
PRESENTATION: 1x1 Amp. With disposable syringe.
Example - 5 Methylcobalamin 500mcg/lml Amp
The Neurologically active form of Vitamin B12
Description '• Methylcobalamin is one of the two active coenzyme forms of vitamin B12 (the other being adenosylcobalamin). It is a co-factor in the enzyme methionine synthase, which functions to transfer methyl groups for the regeneration of methionine from homocysteine, Methylcobalamin is closely involved in foliate metabolism which is pivotal for the synthesis of purines and therefore of deoxyribonucleic acid (DNA). Methylcobalamin also acts as a methyl donor for the synthesis of lecithin, a major component of the myeUn sheath.

Composition * Each Ampoule contains 500 meg of Methylcobalamin in 1ml of the solvent.
PHARMACOLOGY:
1. Methylcobalamin is a kind of endogenous coenzyme B12. Methylcobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.
2. Methylcobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis. Methylcobalamin is better transported to nerve cell organelles than cyanocobalamin in animals. It has been shown in experiments with cells from the brain origin and spinal nerve cells in mice to be involved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utilization and metabohsm of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in animals more than cobamamide does.
3. Methylcobalamin promotes axonal transport and axonal regeneration. Methylcobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from animals models with streptozotocin induced diabetes mellitus. It exhibits neuropathologically and electro physiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine models of axonal degeneration in mice and neuropathies in animals with spontaneous diabetes meUitus.
4. Methylcobalamin promotes Methylcobalamin (Phospholipid synthesis). Methylcobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipid and increases myelination of neurons in animals tissue culture more than cobamamide does.
5. Methylcobalamin restores delayed synaptic transmission and diminished neurotransmitteres to normal. Methylcobalamin, restores end-plate potential induction early by increaing nerve fiber excitability in the crushed sciatic nerve. In addition, Methylcobalamin normalizes diminished brain tissue levels of acetylchohne in animals fed a choHnedeficient diet.
6. Methylcobalamin promotes the maturation and division of erythroblasts, thereby alleviating anemia. It is well known that vitamin B12 deficiency may cause specific megaloblastic anemia. Methylcobalamin promotes nucleic acid synthesis in bone marrow increasing erythrocyte production and promotes the maturation and division of erythroblasts, thereby increasing erythrocyte production Methylcobalamin brings about a rapid recovery of diminished red blood cell, hemoglobin, and hematocrit in vitamin B12 deficient animals.

INDICATIONS : Peripheral Neuropathies : Diabetic Neuropathy, Alcohohc Neuropathy, Drug
iduced Neuropathy, Neuralgia.
Bells Palsy : Megaloblastic anaemia caused by vitamin B12 deficiency - Cancer, Male impotence, Hyperhomocystinemia & Sleep Disturbances.
DOSAGE : Peripheral Neuropathy : The usual dosage for adults is 1 ampoule (500mcg of Methylcobalamin) daily by IM or IV 3 times in a week. The dose may be adjusted depending upon the patients age & symptoms.
Megaloblastic Anaemia '
The usual dosage for adults is 1 ampoule (500mcg of Methylcobalamin) daily by IM or IV 3 times in a week. After 2 months the dose should be reduced to a single administration of 1 amp. At 1-3 months interval for maintenance therapy.
Other Indications- As directed by the physician.
PRECAUTIONS : 1. Adverse Reactions : Adverse reactions were reported in 13 of 2872
patients (0.45%). (At the end of the reexamination period)
(l) Clinically significant adverse reactions (incidence unknown)
Anaphylactoid reaction • Anaphylactoid reaction such as decrease in blood pressure or dyspnea, may occur. Patients should be carefully observed. In the event of such symptoms, treatment should be discontinued immediately and appropriate measures taken.
STORAGE: Store it in a cold, dry place protect from light and moisture.
PRESENTATION: 1x1 Amp. With disposable syringe.
The invention has been explained in relation to specific embodiment. It is inferred that the foregoing description is only illustrative of the present invention and it is not intended that the invention be limited or restrictive thereto. Many other specific embodiments of the present invention will be apparent to one skilled in the art from the foregoing disclosure. All substitution, alterations and modification of the present invention which come within the scope of the following claims are to which the present invention is readily susceptible without departing from the spirit of the invention.

The scope of the invention should therefore be determined not with reference to the above description but should be determined with reference to appended claims along with full scope of equivalents to which such claims are entitled.
We claim

1.

A methylcobalamin composition involving a novel process involved in the manufacture of drug delivery system by way of injectible form comprising the following raw material in their proportion.

Sl.No. Raw Material Qty per ml
1. Methylcobalamin 500 meg
2. Benzyl Alcohol IP 2%
3, Disodium Edta 0.1%
4. Mannitol LP. Pyrogen free 50 mg
5. Water for Injection Ip to 0.1ml

2.

A methylcobalamin composition involving a novel process involved in the manufacture of drug dehvery system by way of injectible form comprising the following raw material in their proportion.

Sl.No. Raw Material Qty per ml
1. Methyl cobalamin 1000 meg
2. Benzyl Alcohol IP 2%
3. Disodium Edta 0.1%
4. Mannitol LP. Pyrogen free 50 mg
5. Water for Injection Ip to 0.1ml

A methylcobalamin composition involving a novel process involved in the manufacture of drug delivery system by way of injectible form comprising the following raw material in their proportion.

SI. No. Raw Material Qty per ml
1. Methyl cobalamin 1500 meg
2. Benzyl Alcohol IP 2%
3. Disodium Edta 0.1%
4. Mannitol LP. Pyrogen free 50 mg
5. Water for Injection Ip to 0.1ml
A methylcobalamin composition involving a novel process involved in the manufacture of drug delivery system by way of injectible for comprising the following raw material in their proportion.

Sl.No. Raw Material Qty per xml
1. Methyl cobalamin 2500 meg
2. Benayl Alcohol IP 2%
3. Disodium Edta 0.1%
4. Mannitol LP. Pyrogen free 50 mg
5. Water for Injection Ip to 0.1ml

5. A methylcobalamin composition involving a novel process involved in the
manufacture of drug delivery system by way of injectable form comprising the
following raw material in their proportion.
a. Collect 90 Lis of WFI in a 100 Lit Processing tank (SS 316) and bubble with, filtered (0.2U) Nitrogen
b. Cool the water to 2-8 Degree Centigrade Temp of WFI: 2-8 oC
c. Add 100 of Disodium EDTA and dissolve
d. Mlx.20 Kg of Benzyl alcohol with WFI of Step 1
e. Dissolve 5.0 kg of Mannitol LP. Pyrogen free
f. Dissolve 72,5 gm Mecobalamin
g. Check the pH, Clarity, and the colour of the final solution.
6. A novel process of manufacturing methylcobalamin in injectable form as
described in the complete specification.