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WO2009066138A2 - Stabilization of vitamin b complex and lidocaine hydrochloride injection - Google Patents

Stabilization of vitamin b complex and lidocaine hydrochloride injection Download PDF

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Publication number
WO2009066138A2
WO2009066138A2 PCT/IB2008/002626 IB2008002626W WO2009066138A2 WO 2009066138 A2 WO2009066138 A2 WO 2009066138A2 IB 2008002626 W IB2008002626 W IB 2008002626W WO 2009066138 A2 WO2009066138 A2 WO 2009066138A2
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Prior art keywords
composition
vitamin
stabilizer
lidocaine
range
Prior art date
Application number
PCT/IB2008/002626
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French (fr)
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WO2009066138A3 (en
Inventor
Sateesh Kumar Chauhan
Surender Kumar Kamal
Deepak Bahri
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Promed Research Centre
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Publication of WO2009066138A2 publication Critical patent/WO2009066138A2/en
Publication of WO2009066138A3 publication Critical patent/WO2009066138A3/en

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the field of formulations and more particularly relates to a stable composition comprising multivitamins for human and veterinary administration.
  • Multivitamin formulations are one of the most common and largely used products - throughout the world and making the formulations more stable will have tremendous industrial applicability.
  • Vitamin B-complex preparation comprises mixture of two or more of solid or crystalline vitamins that are necessary for energy metabolism. These preparations are commonly marketed as solid vitamin products, usually in the form of tablets or as gelatin capsules and parenteral vitamin products, such as intra-muscular injections.
  • vitamin Bi thiamine
  • the potency of the product also decreases markedly with the passage of time. This loss in potency has been shown by chemical and animal tests to result from the actual chemical destruction of the vitamin rather than to any masking or similar effect exerted by other vitamins contained in the preparation.
  • components of vitamin B complex such as Thiamine, riboflavin and cyanacobalamin are light sensitive and prone to oxidation. The solution of these components in combination is not stable if not protected with stabilizers.
  • Vitamins and nutrients are generally sensitive to the effects of temperature, oxygen, and light; a slight change in the molecular structure of a nutrient can render it biologically ineffective.
  • the following vitamins are known to be specifically vulnerable to degradation by UV light: Vitamin A, B 2 (riboflavin), Be, B 12 , and folic acid. Light also accelerates the destructive interaction between vitamins
  • the degradation may be inhibited by adding various stabilizing agents such as sodium formaldehyde sulphoxylate, propyl gallate, glycine, butylated ' hydroxyanisole, butylated hydroxytoulene in concentration dependent manner.
  • stabilizing agents such as sodium formaldehyde sulphoxylate, propyl gallate, glycine, butylated ' hydroxyanisole, butylated hydroxytoulene in concentration dependent manner.
  • US patent 5,173,4808 discloses a method for stabilization of an injectable aqueous composition comprising folic acid by adding stabilizing agents such as tromethamine and monothioglycerol. Considering the shortcomings of the prior art, there is a need to provide a stabilized composition comprising vitamins especially vitamin B.
  • the principle objective of the present invention is to provide a composition of vitamin B complex. Another objective of the present invention is to enhance the stability of vitamin B complex composition and increase its shelf life.
  • the present invention provides a stable composition
  • a stable composition comprising vitamin B l (thiamin), vitamin B6 (pyridoxine), vitamin B 12 (cyanocobalamine), a local anesthetic agent together with one or more stabilizers.
  • the present invention provides a stable Vitamin B complex composition
  • a stable Vitamin B complex composition comprising vitamin B 1 , vitamin B 6 , Vitamin B 12 , a local anesthetic agent in combination with at least two stabilizers.
  • the local anesthetic agent may be selected from a group comprising of anesthetics such as like benzociane, chloroprocaine, cocaine, procaine, tetracaine; or amides like bupivacaine, levobupivaciane, lidocaine, ropivacaine, articaine, trimecaine, prilocaine.
  • anesthetics such as like benzociane, chloroprocaine, cocaine, procaine, tetracaine; or amides like bupivacaine, levobupivaciane, lidocaine, ropivacaine, articaine, trimecaine, prilocaine.
  • the local anesthetic agent is lidocaine or its salt.
  • the amount of the anaesthetic may be in range of lOmg to 50 mg per ml.
  • the stabilizers are selected from the group comprising a chelating agent, organic acid and cyanoferrate and more preferably stabilizers are ethylene diamine tetra acetic acid, malic acid and potassium ferrocynide.
  • the amount of stabilizer may be in a range of 0.005-1.0%, 0.05-5% or 0.005-1.0%. More preferably the composition ethylene diamine tetra acetic acid (EDTA) is 0.10 %, malic acid is 0.5% and potassium ferrocynide is 0.1%.
  • EDTA ethylene diamine tetra acetic acid
  • the composition of the invention exhibits synergistic effect in that the vitamins in combination with the anesthetic agent and the stabilizers are synergistic. As shown in Table 1, the combination of EDTA with potassium hexaferrocyanide exhibited the best synergistic effect. The composition exhibits both physical stability and prevents the degradation of Vitamin B 12. The combination containing malic acid, potassium hexaferrocyanide and EDTA showed synergistic effect, better than the combination of two.
  • the samples were kept in a stability chamber at 4O 0 C and tested after 4 weeks of exposure. The results were compared with initial sample.
  • the comparative formulations are provided in table-1.
  • the product without any stabilizer is not stable as the sample shows turbidity.
  • the product formulated individually with/stabilizers such as Potassium hexa ferrocyanide, disodium EDTA and malic acid showed physical instability and degradation of vitamin B 12, respectively.
  • the composition containing combinations of malic acid with potassium ferrocyanide and disodium EDTA with Malic acids were also ineffective, rendering the composition physically unstable or unable to prevent degradation of vitamin B 12.
  • the composition may be used in the symptomatic treatment of nervous diseases of different origins such as neuritis, neuralgia, polyneuropathy, myalgia, radicular syndromes, retrobulbar neuritis, herpes zoster varicellosus, paresis of facial nerve; and in systemic nervous diseases caused by vitamin Bl and B6 deficiency.
  • nervous diseases of different origins such as neuritis, neuralgia, polyneuropathy, myalgia, radicular syndromes, retrobulbar neuritis, herpes zoster varicellosus, paresis of facial nerve; and in systemic nervous diseases caused by vitamin Bl and B6 deficiency.
  • the above table describes the various trials carried out by using different combination of stabilizers.
  • the stabilizers present in the various formulations are
  • composition of the present invention may be prepared by a process comprising
  • the invention provides a composition which is stable. Hence as in the prior art, there is no need to add "overages" to the compositions thus saving substantial costs in manufacture.
  • composition is stable and thus has an extended shelf life. Hence the storage and transportation of the compositions are made simple and easy.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The Present Invention provides a stable parenteral composition of Vitamin B Complex & Lidocaine Hydrochloride which is stabilized by synergistic combination of stabilizers such as DL-malic acid, Disodium Edetate and Potassium Hexacyanoferrate III and process thereof.

Description

STABILIZATION OF VITAMIN B COMPLEX AND LIDOCAINE HYDROCHLORIDE INJECTION
Field of invention:
The present invention relates to the field of formulations and more particularly relates to a stable composition comprising multivitamins for human and veterinary administration.
Background and Prior Art:
Multivitamin formulations are one of the most common and largely used products - throughout the world and making the formulations more stable will have tremendous industrial applicability.
Vitamin B-complex preparation comprises mixture of two or more of solid or crystalline vitamins that are necessary for energy metabolism. These preparations are commonly marketed as solid vitamin products, usually in the form of tablets or as gelatin capsules and parenteral vitamin products, such as intra-muscular injections.
It is also well known that in many multiple vitamin preparations, especially parenteral compositions, containing vitamin Bi (thiamine) undergoes decomposition which may cause loss of potency and instability of other vitamins such as vitamin Bi2. The potency of the product also decreases markedly with the passage of time. This loss in potency has been shown by chemical and animal tests to result from the actual chemical destruction of the vitamin rather than to any masking or similar effect exerted by other vitamins contained in the preparation. One of the reasons is that components of vitamin B complex such as Thiamine, riboflavin and cyanacobalamin are light sensitive and prone to oxidation. The solution of these components in combination is not stable if not protected with stabilizers.
Vitamins and nutrients are generally sensitive to the effects of temperature, oxygen, and light; a slight change in the molecular structure of a nutrient can render it biologically ineffective. The following vitamins are known to be specifically vulnerable to degradation by UV light: Vitamin A, B2 (riboflavin), Be, B12, and folic acid. Light also accelerates the destructive interaction between vitamins
(Jittp://mostproject.org/Updates_Feb05/Stability.pdf).
In order to ensure that one hundred percent of the ingredient amount specified on the ■ label of the formulation is available to the patient on the specified expiration date o the formulation, larger quantities of the essential ingredient is added. This ensures that the expected degradation of vitamins is compensated by additional amount of the material in the formulation. The addition of excessive material to counteract loss by degradation is known as "overages".
An overage of <50% of vitamin content for water soluble vitamin is permitted. http://mccza.eom/documents/2.08%20Post-reg%20amendments%20Nov06%20v3.doc.
The addition of overages renders the process of preparation of vitamins and vitamin preparation costly, as more amount of vitamins are required in the process.
Alternatively, instead of adding overages to counteract the loss of vitamin by degradation, the degradation may be inhibited by adding various stabilizing agents such as sodium formaldehyde sulphoxylate, propyl gallate, glycine, butylated ' hydroxyanisole, butylated hydroxytoulene in concentration dependent manner.
Prior art discloses the use of stabilizing agents either individually or in combination. Thus it appears that there are no stable preparations comprising vitamin B.
US patent 5,173,488, discloses a method for stabilization of an injectable aqueous composition comprising folic acid by adding stabilizing agents such as tromethamine and monothioglycerol. Considering the shortcomings of the prior art, there is a need to provide a stabilized composition comprising vitamins especially vitamin B.
Objects of the invention:
The principle objective of the present invention is to provide a composition of vitamin B complex. Another objective of the present invention is to enhance the stability of vitamin B complex composition and increase its shelf life. Statement of the invention:
The present invention provides a stable composition comprising vitamin B l (thiamin), vitamin B6 (pyridoxine), vitamin B 12 (cyanocobalamine), a local anesthetic agent together with one or more stabilizers.
Detailed description of the invention:
Accordingly the present invention provides a stable Vitamin B complex composition comprising vitamin B1, vitamin B6, Vitamin B12, a local anesthetic agent in combination with at least two stabilizers.
The local anesthetic agent may be selected from a group comprising of anesthetics such as like benzociane, chloroprocaine, cocaine, procaine, tetracaine; or amides like bupivacaine, levobupivaciane, lidocaine, ropivacaine, articaine, trimecaine, prilocaine.
Preferably the local anesthetic agent is lidocaine or its salt. The amount of the anaesthetic may be in range of lOmg to 50 mg per ml. The stabilizers are selected from the group comprising a chelating agent, organic acid and cyanoferrate and more preferably stabilizers are ethylene diamine tetra acetic acid, malic acid and potassium ferrocynide. The amount of stabilizer may be in a range of 0.005-1.0%, 0.05-5% or 0.005-1.0%. More preferably the composition ethylene diamine tetra acetic acid (EDTA) is 0.10 %, malic acid is 0.5% and potassium ferrocynide is 0.1%.
The concentration of vitamins per ml of the solution,
Figure imgf000004_0001
The composition of the invention exhibits synergistic effect in that the vitamins in combination with the anesthetic agent and the stabilizers are synergistic. As shown in Table 1, the combination of EDTA with potassium hexaferrocyanide exhibited the best synergistic effect. The composition exhibits both physical stability and prevents the degradation of Vitamin B 12. The combination containing malic acid, potassium hexaferrocyanide and EDTA showed synergistic effect, better than the combination of two.
The samples were kept in a stability chamber at 4O0C and tested after 4 weeks of exposure. The results were compared with initial sample. The comparative formulations are provided in table-1. The product without any stabilizer is not stable as the sample shows turbidity. The product formulated individually with/stabilizers such as Potassium hexa ferrocyanide, disodium EDTA and malic acid showed physical instability and degradation of vitamin B 12, respectively. The composition containing combinations of malic acid with potassium ferrocyanide and disodium EDTA with Malic acids were also ineffective, rendering the composition physically unstable or unable to prevent degradation of vitamin B 12.
The composition may be used in the symptomatic treatment of nervous diseases of different origins such as neuritis, neuralgia, polyneuropathy, myalgia, radicular syndromes, retrobulbar neuritis, herpes zoster varicellosus, paresis of facial nerve; and in systemic nervous diseases caused by vitamin Bl and B6 deficiency.
Table -1
Figure imgf000006_0001
* Assa\ not performed as sample is phvsicalK not stable
All \ alues expressed as Mean ± SE
The formula for calculating Standard error of mean is S D / V no of sample
Table- 2
c
Figure imgf000007_0001
\
Figure imgf000007_0002
The above table describes the various trials carried out by using different combination of stabilizers. The stabilizers present in the various formulations are
PRIE005 30- No stablizer
PRIE005 31- EDTA
PRIE005 33- DL-malic acid
PRIE005 34- EDTA and Potassium cyanohexaferrate III
PRJE005 36- EDTA and DL-malic acid
PRIE005 43- Potassium cyanohexaferrate III and DL-malic acid
PRIE005 44- Potassium cyanohexaferrate III and EDTA
PRJE005 45- Potassium cyanohexaferrate III, DL-malic acid and EDTA
In another embodiment, the composition of the present invention may be prepared by a process comprising
a. dissolving stabilizers in aqueous or non-aqueous medium b. adding vitamins to solution as in step a) c. Filtering the solution as in step b) d. packaging in suitable bottles
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
Example 1:
10 mg of DL malic acid, 2 mg of potassium hexa ferrocynate, 40 ml of benzyl alcohol and 2 mg disodium EDTA were dissolved in water for injection one by one with stirring and into it lOOmg vitamin of Bi, lOOmg of B6, 1000 meg Of Bi2 and 20 mg of lidocaine hydrochloride were added to obtain a clear solution. The pH of the solution was adjusted in between 3.8 to 4.2 and the solution is filtered through 0.2 micron filter and after filtration the solution was filled in amber glass ampoules and then sealed.
Example 2
10 mg of DL malic acid, 2 mg of potassium hexa ferrocynanide and 40 ml of benzyl alcohol were dissolved in water for injection one by one with stirring and into it lOOmg vitamin of Bi, lOOmg of B6, 1000 meg of Bi2 and 20 mg of lidocaine hydrochloride were added to obtain clear solution. The pH of the solution was adjusted in between 3.8 to 4.2 and the solution is filtered through 0.2 micron filter and after filtration the solution was filled in amber glass ampoules and then sealed.
Example 3
10 mg of DL malic acid, 2 mg of potassium hexa ferrocynate and 40 ml of benzyl alcohol were dissolved in a mixture of propylene glycol and water for injection one by one with stirring and into it lOOmg vitamin of Bi, lOOmg of B6, 1000 meg of B 12 and 20 mg of lidocaine hydrochloride were added to obtain clear solution. The pH of the solution was adjusted in between 3.8 to 4.2 and the solution is filtered through 0.2 micron filter and after filtration the solution was filled in amber glass ampoules and then sealed.
Advantages
The invention provides a composition which is stable. Hence as in the prior art, there is no need to add "overages" to the compositions thus saving substantial costs in manufacture.
Another advantage of the invention is that the composition is stable and thus has an extended shelf life. Hence the storage and transportation of the compositions are made simple and easy.

Claims

We Claim:
1. A composition comprising vitamin Bl(Thiamin), vitamin B6 (pyridoxine). Vitamin B 12 (cyanocobalamin), a local anesthetic agent together with one or more stabilizers.
2. A composition as claimed in claim 1, wherein the local anesthetic is selected from a group comprising ester selected from benzociane, chloroprocaine, cocaine, procaine, and tetracaine or amide selected from bupivacaine, levobupivaciane, lidocaine, ropivacaine, articaine, trimecaine and prilocaine.
3. A composition as claimed in claim 2, wherein the local anesthetic agent is lidocaine or salt thereof.
4. A composition as claimed in claim 1, wherein the lidocaine is present in range of 1 Omg to 50 mg per ml.
5. A composition as claimed in claim 1, wherein the stabilizer is selected from the group comprising a chelating agent, an organic acid and a cyanoferrate.
6. A composition as claimed in claim 5, wherein the stabilizer is ethylene diamine tetra acetic acid, malic acid and potassium ferrocynide.
7. A composition as claimed in claim 5, wherein the amount of stabilizer is
Figure imgf000010_0001
8. A composition as claimed in claim 5, wherein preferably, the amount of stabilizer is:
Figure imgf000010_0002
9. A composition as claimed in claim 1, wherein the per ml concentration of vitamin B 1 is in a range of 50 tolOO.O mg, Vitamin B6 in a range of 50 to 100.0 mg and Vitamin B12 in range of 500 to 1000 meg.
10. A composition as claimed in claim wherein the solvent is an aqueous or a non-aqueous or a mixture of both.
11. A process of preparing composition as claimed in claim 1, wherein the said process comprises a. dissolving stabilizers in aqueous or non-aqueous medium b. adding vitamins to solution as in step a) c. filtering the solution as in step b) d. packaging in suitable bottles
12. Use of pharmaceutical composition as claimed in claim 1 for the prophylaxis and treatment of nervous disorders.
PCT/IB2008/002626 2007-11-22 2008-10-06 Stabilization of vitamin b complex and lidocaine hydrochloride injection WO2009066138A2 (en)

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IN2441DE2007 2007-11-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011145914A1 (en) * 2010-05-19 2011-11-24 Alejandra Zepeda Flores Lidocaine as a transformer and producer of transformed complexes of drugs delivered in nano-dosages using injection implants as prolonged release devices

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BG104880A (en) * 2000-10-24 2002-04-30 Иван ХРИСТОВ Medicamentous preparation for multiple sclerosis treatment
AU2096002A (en) * 2000-12-08 2002-06-18 Pieter Theo Ernst Therapeutic treatment
RU2225707C1 (en) * 2003-03-04 2004-03-20 Закрытое акционерное общество "Брынцалов-А" Pharmaceutical composition eliciting analgetic effect, improving blood supply, stimulating regeneration of nervous tissue and anti-allergic effect

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011145914A1 (en) * 2010-05-19 2011-11-24 Alejandra Zepeda Flores Lidocaine as a transformer and producer of transformed complexes of drugs delivered in nano-dosages using injection implants as prolonged release devices

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