|Title of Invention||
A PHARMACEUTICAL FORMULATION OF CHROMIUM INSULIN INJECTION (SUSPENSION) AND ITS PREPARATION
|Abstract||The present invention relates to a novel formulation of chromium insulin injection (suspension) and its method of preparation which comprises porcine insulin 60-120 mg, chromium picolinate 5-25 ml, acetate buffer solution 5-15 ml, methyl paraben (0.1-0.2% w/v),water to make final volume 50 ml and process of manufacturing thereof. The manufacturing process is as such that the final pH 4.4-4.5 of a novel formulation of chromium insulin injection (suspension) is achieved. This invention provides useful and better insulin formulation for diabetes and insulin resistance. It has better therapeutic potential in atherosclerosis, and other complications associated with diabetes. 15 JAN 2007|
|Full Text||FORM - 2
THE PATENTS ACT, 1970
(39 of 1970) COMPLETE SPECIFICATION
(See section 10; rule 13)
1. A PHARMACEUTICAL FORMULATION OF CHROMIUM INSULIN INJECTION (SUSPENSION) AND ITS PREPARATION
2. (a) L. M. COLLEGE OF PHARMACY,
run by Ahmedabad Education Society, a Registered Trust at
(b) P.O. Box No. 4011, Navarangpura, Ahmedabad-3 80009. Gujarat State, India.
(c) Nationality: Indian
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
The present invention relates to formulation of insulin containing chromium in suspension form, which is stable and to be used as antidiabetic agent and its method of preparation.
A pharmaceutical formulation of chromium insulin injection (suspension) comprises porcine insulin as an active ingredient and chromium picolinate as second active ingredient. The State Of Art
Insulin is produced by p-cells of endocrine pancreatic islets, which helps in glucose metabolism. In diabetic condition production of insulin from the P-cells of pancreatic islets is affected. So insulin therapy is given to diabetic patients since years.
Trace elements play important role in altering conditions of hyperglycemias, some of the trace elements which have proven beneficial activity in diabetes are zinc, chromium, vanadium, molybdenum and selenium. Chromium, in the form of chromium chloride and chromium picolinate is widely established to have beneficial effects in diabetes in reducing hyperglycemia and also associated hyperlipidemia.
Chromium (Cr), is a first-series transition element of group VI B which is present ubiquitously in water, soil and living matter (Schroeder et
al., 1963). Insulin becomes inactive as chromium is depleted because chromium functions as a cofactor for insulin. It binds to the insulin receptor and potentiates many, and perhaps all, of its functions (Boyle et al., Chromium Depletion and the Pathogenesis of Diabetes and Atherosclerosis, Southern Medical Journal 70(12): 1449-1453, 1977). Principle energy sources of the body are carbohydrate (in the form of glucose), proteins and fatty acids. Chromium works with insulin to metabolize carbohydrates, fats and proteins. When chromium depletion results, the body must depend on lipid metabolism to fulfill energy requirements which causes increase production of acetyl-Co A and ketone bodies. Acetyl-Co A is key ingredient for cholesterol biosynthesis and the condition above describe leads to hypercholesterolemia (Boyle et al., Chromium Depletion and the Pathogenesis of Diabetes and Atherosclerosis, Southern Medical Journal 70(12): 1449-1453,1977).
Chromium picolinate is a biologically active form of chromium. Chromium picolinate's preparation, effects and applications are described in many scientific publications. G.W. Evans and D.J. Pouchnik in J. Inorgan. Biochem.,49, 177 (1993) described chromium picolinate general preparation, chemical and biological properties, its clinical effect on insulin
metabolism has been indicated by G. W. Evands in Int. J. Biosocial Med. Res., 11, 163 (1989) and its lipid lowering activity has been reported by R. I. Press in West. J. Med., 152, 41 (1990).
Patent US2002081315 describes a composition for treating insulin-dependent diabetes, reducing body fat, improving insulin sensitivity, reducing hyperglycemia, and reducing hypercholesterolemia with at least one chromium complex and a conjugated fatty acid or conjugated fatty alcohol. Here conjugated fatty acids or conjugated fatty alcohol functions synergistically with a chromium complex to facilitate glucose uptake and usage by cells.
US patent 6,143,301 discloses chromium picolinate compositions and uses thereof. The composition of inventions comprising chromic tripicolinate or chromic polyniconinate in combination with at least one of a cyclooxygenase inhibitor, an acid, a mucolyitc and a salicin-containing herb.
US patent 6,323,192 relates to composition of chromic tripicolinate or chromic polynicotinate in the form of enteric-coated tablets, capsules or microbeads, optionally in combination with nicotinic acid, picolinic acid or both nicotinic acid and picolinic acid. The invention further comprises a
cyclooxygenase inhibitor, and acid, a mucolytic, a salicin-containing herb, or combination of thereof.
US patent 2002098247 depicts method of improving insulin sensitivity in a subject in need thereof including administering to a subject a pharmaceutically effective dose of alpha-lipoic acid in conjugation with at least one chromium complex.
All the above stated prior inventions are used for improving insulin sensitivity. In these inventions insulin is given separately so the effect required is no up to mark. Also due to this reason cost of diabetic treatment is tremendously increased.Administration of insulin dose with other medicaments are inconvenient.
Patent EP0016496 describes chromium (III) tris-acetylacetonate, as a dietary supplement and pharmaceutical agent used in conjunction with insulin therapy for treating diabetes. This composition is made for oral administration so efficiency depends upon absorption rate of chromium (III) tris-acetylacetonate and insulin which is one limitation of this invention.
To overcome these limitations of insulin formulation occurred in above stated patents, there is need of formulation which reduces the
frequent pricking episodes to patient, affordable and stable formulation that regulate metabolism of insulin.
In the present invention a novel formulation of chromium insulin in suspension form is prepared and on continuous usage prevents further dose of insulin and maintain glycemic control on diabetic patients. Detail Description of invention:
The main object of the present invention is formulation of chromium insulin injection (suspension) and its method of preparation.
The insulin dependent diabetes mellitus patients are required to administer insulin in form of injection, tablets etc. Application of insulin injections to diabetic patients is a painful exercise, suspension of chromium insulin prepared in the present invention refrains the painful condition to patients.
Porcine insulin is used as active ingredient and chromium picolinate as trace element which acts as cofactor for insulin. One another object of the present invention is development of insulin formulation which on continuous usage until the diabetic control prevents further use of insulin and maintains glycemic control.
It is known that chromium deficiency is associated with the blood sugar irregularities of diabetes. Recent studies have demonstrated that chromium is effective in treating various types of diabetes including type-1 and type-2, gestational and steroid induced diabetes.
In preparation of a novel formulation of chromium insulin injection (suspension) incorporates acetate buffer for adjusting pH, methyl paraben as preservative and water to make final volume of suspension.
A novel formulation of chromium insulin injection (suspension) comprises 60-120 mg porcine insulin, 5-25 ml chromium picolinate (0.03-0.07% w/v), 5-15 ml acetate buffer, 0.1-0.2% w/v methyl paraben and water to make final volume 50 ml of suspension.
Embodiment of the invention relates to process for formulation of insulin with chromium injection in suspension form, which is stable and to be useful as antidiabetic agent which involves following steps of:
(a) Porcine insulin (60-120 mg) is taken in a 100 ml beaker.
(b) To this 5-25 ml of chromium picolinate (0.03-0.07% w/v) is added gradually with stirring to get clear solution.
(c) 5-15 ml of acetate buffer solution is added into step no (b) with continuous stirring and suspension is developed.
(d) Suspension pH is found to be 4.3-4.4.
(e) 8-14 ml of preservative solution (methyl paraben 0.1-0.2% w/v) is added and stirred well.
(f) Final volume is made up to 50 ml with water for injection.
(g) The final pH of above injection (suspension) is found to be 4.4-4.5.
(h) The above formulation is prepared at the strength of 40 IU/ml.
(i) The above formulation is prepared in aseptic conditions (Class 100
environment) and stock solutions required for the above formulation
are filtered through 0.22 \i membrane filter.
The glass vials used for novel formulation of chromium insulin injection (suspension) are sterilized by dry heat sterilization method at temperature 250° centigrade for 90 minutes. The rubber stoppers are sterilized by autoclave at 121° centigrade for 30 min at 15 Psig. Assay of the formulation for insulin content by HPLC method:
The assay for the insulin content in the novel formulation of chromium insulin injection (suspension) is carried out using HPLC (High Performance Liquid Chromatography) particularly with high molecular weight protein (HMWP) column and the mobile phase used is 2.5 molar acetic acid. The flow rate is 2 ml per min. The samples are analyzed using
UV detector at 280 nm. The injection volume is 50ul. The standard porcine insulin is kept as reference standard for the analysis of the test formulation. Estimation of chromium in the formulation:
The total chromium content of the novel formulation of chromium insulin injection (suspension) is estimated by using atomic absorption spectroscopy. The lamp used for determination of chromium is chromium (deuterium) at the wave length of 357.9 nm and lamp current is 6 mv and burner used is air-acetylene. The chromium content is found to be 12.42 Hg/ml. Stability studies:
On going stability studies are carried out for the novel formulation of chromium insulin injection (suspension) at 2-8° centigrade in refrigerator as per International conference on hormonization (ICH) guidelines. The samples are kept for stability studies at the intervals of 0 month and 6 months. Macroscopy, microscopy, clarity test, assay for insulin content, pH, chromium in total, and methyl paraben content are used for stability test and the present formulation of chromium insulin suspension.
The invention is illustrated more in detail in the following example.
Example 1 : A process for formulation of insulin chromium injection
60-120 mg of porcine insulin is taken in 100 ml beaker; to this 5-25 ml chromium picolinate solution (0.03-0.07 %w/v) is added gradually with stirring to get clear solution. 5-15 ml of acetate buffer solution is added to above solution with continuous stirring and suspension is developed. The pH of the suspension is found to be 4.3-4.4; to the above solution 8-14 ml of methyl paraben (0.1-0.2% w/v) is added and stirred well. Final volume is made up to 50 ml with water for injection (WFI). The final pH of the formulation is found to 4.4-4.5 and the formulation is prepared at the strength of 40 IU/ml in aseptic conditions (Class 100 environment) and the stock solutions required for the chromium insulin injection are filtered through 0.22u membrane filter. The overall area conditions are validated as per WHO and US FDA guidelines to get the consistency and reproducible quality of above injection to meet predetermined standards.
A novel formulation of chromium insulin injection (suspension) provides useful and better insulin formulation for diabetes and insulin
1. A pharmaceutical formulation of chromium insulin injection (suspension) comprises porcine insulin 60-120 mg, chromium picolinate (0.03-0.07% w/v) 5-25 ml , acetate buffer solution 5-15 ml, methyl paraben as preservative solution (0.1-0.2% w/v) 8-14 ml, and water for injection (WFI) to make final volume 50 ml.
2. A process for preparation of a pharmaceutical formulation of chromium insulin injection (suspension) and its method of preparation comprising the steps of:
a. taking 60-120 mg of porcine insulin in a 100 ml beaker;
b. gradually adding 5-25 ml of chromium picolinate (0.03-
0.07% w/v) and stirring it to get clear solution;
c. adding 5-15 ml of acetate buffer solution in the solution
obtained in (b) and stirring continuously to form suspension;
d. finding pH of suspension obtained in (c) to be 4.3-4.4;
e. adding 8-14 ml of methyl paraben (0.1-0.2% w/v) and
f. making the final volume 50 ml with water for injection
g. finding the final pH of the above injection (suspension) 4.4-4.5.
3. A process for preparation of a pharmaceutical formulation according to claim 2, wherein stock solutions require for the formulation are filtered through 0.22^1 membrane filter.
4. A process for preparation of a pharmaceutical formulation according to claim 2, wherein formulation is prepared under aseptic conditions (Class 100 environment).
5. A pharmaceutical formulation of chromium insulin injection (suspension) as substantially herein described with foregoing description, and example.
6. A process for preparation of a pharmaceutical formulation as substantially herein described with foregoing description, and example.
|Indian Patent Application Number||1120/MUM/2004|
|PG Journal Number||42/2008|
|Date of Filing||19-Oct-2004|
|Name of Patentee||L. M. COLLEGE OF PHARMACY|
|Applicant Address||P.O.BOX. NO.4011, NAVARANGPURA, AHMEDABAD 380009. GUJARAT STATE, INDIA.|
|PCT International Classification Number||A61K 31/555|
|PCT International Application Number||N/A|
|PCT International Filing date|