WO2003079819A1

WO2003079819A1 - Dietary supplement composition and a process of manufacturing said composition

Info

Publication number: WO2003079819A1
Application number: PCT/IN2002/000236
Authority: WO
Inventors: S. B. Khanolkar
Original assignee: ANGLO FRENCH DRUGS AND INDUSTRIES Ltd
Current assignee: ANGLO FRENCH DRUGS AND INDUSTRIES Ltd
Priority date: 2002-03-27
Filing date: 2002-12-16
Publication date: 2003-10-02
Anticipated expiration: 2004-09-27

Abstract

A novel dietary supplement composition having the following ingredients in their ideal proportion: Alpha Lipoic Acid 133 mg Inositol 250 mg Elemental Chromium 30 mg forming a synergistic composition. A novel process of manufacturing dietary supplement comprising the following steps. (a) Preparation of granulation solution, (b) Granulation of alfa lipoic acid, (c) Sifting and Mixing, (d) Blending, (e) Collection of granules in a clean drum having double polythene bag and (f) Filling in capsules.

Description

DIETARY SUPPLEMENT COMPOSITION AND A PROCESS OF MANUFACTURING SAID COMPOSITION.

FIELD OF INVENTION

This invention in general relates to human necessities and health care system. More particularly this invention relates to a dietary supplement composition. Precisely this invention relates to a novel dietary supplement composition for treating diabetic neuropathy patients. Accordingly this invention relates to a novel dietary supplement composition and a process of manufacturing the said composition.

PRIOR ART DISCLOSURE

Diabetic neuropathy is a major clinical problem imposing a tremendous burden on the worldwide diabetic population as well as the health care system. It is widely recognized that over 50% of people with diabetes millinus eventually develop clinical symptoms attributable to neuropathy. On neurophysiological testing, over 90% of long-term diabetics exhibit evidence of nerve damage. Moreover, neuropathic foot ulceration is one of the commonest causes of hospital admission and lower limb amputation among the diabetic patients.

While good glycemic control may slow down development of this complication, many patients who are well-controlled still develop severe neuropathy and its unwelcome sequelae; in some others normoglycemia itself is clinically difficult to achieve. There is, therefore, a pressing need for new therapies and new medicinal composition or drug.

It is to be noted that an earnest attempt has been made to explain the merits and the limitations of the existing therapeutic modalities. Several new approaches to treatments, notably Alpha Lipoic Acid, Aldose Reductase Inhibitors and Gamma-Linolenic Acid are currently being investigated. This monograph by way of prior art investigation concisely reviews the clinical problem of diabetic neuropathy and discusses the new therapeutic approach, in particular.

Further it is to be noted that diabetes mellitus is globally assuming an alarming pandemic proportion due to various factors like sedentary lifestyle, inappropriate diet, stressful environment and unhealthy indulgence in risk-prone activities by the rapidly growing worldwide population. With the over-increasing segment of diabetic population, inevitably there is also an increased burden of diabetes-associated complications like diabetic neuropathy, cataractogenesis, diabetic nephropathy, diabetic retinopathy, coronary and cerebral artery disease and related morbid outcomes. Persistent hyperglycemia consequent to poor glycemic control, myo-inositol depletion and oxidative stress, are now considered to be the key pathogenic factors of utmost relevance in the causation of diabetic neuropathy and related complications. Being aware of this, the routine use of novel Dietary supplement as a therapeutic adjunct to anti-diabetic drugs, synergistically improves glycemic control, myo-inositol stores and anti-oxidant status to overall favourably effect therapeutic outcomes while managing diabetes, diabetic nephropathy, and related complications. This novel approach has a high potential to offer better quality of life to millions of diabetics the world over.

SUMMARY OF INVENTION

Reference is made to this novel Dietary supplement as a viable therapeutic option. This novel drug is a synergistic combination of a Lipoic acid, Chromium and Inositol that has a substantial potential to ameliorate neuropathic symptoms by collectively addressing the underlying pathological factors like oxidative stress, glycemic load and tissue - myoinositol depletion. In future as well, combinations of other new drugs that produce such synergistic effect should be developed so that the therapeutic armamentarium against diabetic complications gets further strengthened.

5. The primary object of the invention is to invent a novel dietary supplement composition for preventing diabetes mellitus and treating diabetic neuropathy patients.

It is another object of the invention to invent a novel dietary supplement composition which is effective, does not produce any side 10. effect.

Further objects of the invention will be evident from the ensuing description.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

At the outset of the description which follows it is to be understood 20. that ensuing description only illustrate a particular form of this invention However, such particular form is only an exemplary embodiment, and without intending the 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 and not intended to be taken 25. restrictively.

Now the invention will be described in detail in the following pages of the specification. The nature of the invention will be described in detail and the manner of performing the invention is described in detail. Composition of the novel Dietary Supplement:

Each capsule contains ; Exact and Ideal Composition

Alpha Lipoic Acid 133 mg

Inositol 250 mg

Elemental Chromium 30 mg

(as Chromium picolinate)

The various constituents of the Dietary supplement are described in the following pages of the provisional specifications.

Alpha Lipoic Acid; Oxidative stress is now considered, among others, an important pathogenic factors contributing to chronic diabetic complications. Oxidative stress results in both glucose auto-oxidation and glycation, including the formation of advanced glycation and products, super oxide, hydrogen peroxide and hydroxyl radicals collectively known as reactive Oxygen Species (ROS). Many of the complications of diabetes including polyneuropathy and cataract formation appear to be mediated by

ROS.

Alpha Lipoic Acid is a natural anti-oxidant currently being recognized as having unique abilities to prevent and treat diabetic neuropathy and related complications. Besides being an anti-oxidant, it helps the body enhance its glucose uptake and also helps to regenerate

Nitamin C and Nitamin E. Further, it is also demonstrated to increase intracellular glutathione and coenzyme Q10 and reduce glycosylated hemoglobin.

Free radicals are continuously formed in the body as unwelcome byproducts of biochemical processes which could cause cumulative tissue damage to culminate in cataracts, neuropathy, nephropathy, retinopathy and cardiovascular disease. As for countering diabetic neuropathy and related complications, Alpha Lipoic Acid exerts its beneficial effect by inhibiting glycation of nerve proteins and scavenging free radicals which, if left unchecked, might lead to worsening of paresthesiae, loss of sensation, 5 unrecognized local trauma, refractory infections, pedal ulcers, progressive gangrene and eventual limb amputation.

Ziegler et al have demonstrated in their study that oral treatment with 800 mg/day of Alpha Lipoic Acid, for 4 months, can improve cardiac autonomic neuropathy in NTJDDM patients. Several other studies point out 10 that Alpha Lipoic Acid, at a daily dosage of 350-600 mg. is safe and effective in reducing symptoms of peripheral neuropathy in diabetic patients. Clinically Alpha Lipoic Acid is an important therapeutic adjunct that has immense potential to prevent and treat neuropathy and other diabetic associated complications like retinopathy, cataract, nephropathy, and cardiovascular diseases.

15 Inositol.Based on several experimental and clinical studies implicating the relationship between depletion of nerve myo-inositol concentration and chronic hyperglycermia, supplementary inositol along with good glycemic control has a very high potential to improve nerve function in diabetic neuropathy patients. Available evidence indicates that a deficient

20. myo-inositol - related nerve Na+=K+ATPase deficit is responsible for the acute reversible slowing of nerve conduction in diabetic neuropathy. It is ideally desirable to advocate the supplementary inositol intake in the range of 500mg-1000mg daily. It is very well absorbed from the gastrointestinal tract and easily distributed into various tissues. Since inositol

25. supplementation in trial studies has shown improvement in the nerve N+=K+ATPase activity and nerve function, its beneficial role in diabetic neuropathy appears to be utmost therapeutic importance. Chromium: Chromium is an essential trace element that potentiates insulin action thus influencing carbohydrate, lipid and protein metabolism. It potentiates insulin action possibly by optimizing the number of membrane insulin receptors or their interaction with insulin, or both Chromium is also suggested to be an important component of Glucose Tolerance Factor (GTF) which is crucial for substance glucose transfer across the cell membrane and proper glucose utilization. Daily requirement of Chromium is about 50-20 meg. Chromium deficiency features include insulin-resistant hyperglycemia, weight loss, ataxia, peripheral neuropathy and encephalopathy. Given the important of chromium in relation to glycemic control, chromium supplementation as well makes it that much more relevant to maintain euglycemia and prevent hyperglycemia-related complications.

In view of the fact that Alpha Lipoic Acid, Inositol and Chromium collectively have a substantial relevance to maintaining desirables euglycemia, adequate myo-inositol stores and sound anti-oxidant defense in the clinical management of diabetes, diabetic neuropathy and related complications, the combination of the above nutritional supplements has been deligently designed to optimally synergise their benefits to comprehensively effect favourable therapeutic outcomes.

Safety Profile: This novel product is a safe dietary supplement the individual components of which have been in use for several decades with a good tolerability profile. However, minor side effects like loose stools, nausea stomach discomfort and allergic skin reactions may rarely occur in individuals intolerant to the ingredients in the dietary supplement. It is contraindicated in those with the history of hypersensitivity to any of the ingredients present in this preparation. Hypoglycemic symptoms can occur in diabetics and a consequence of improved glucose utilization. It is always prudent to monitor blood glucose levels initially while starting this dietary. supplement in diabetics , for Alpha Lipoic Acid and Chromium are known to improve glucose utilization which consequently necessitates downward anti-diabetic dosage titration. Concurrent ingestion of iron, zinc and calcium preparation with this dietary supplement is not recommended.

Indications: This novel product will be indicated as a dietary supplement in the management of diabetes mellitus to prevent and treat diabetic neuropathy and related complications.

Recommended Dosage: It is generally recommended to start 1-2 caps of this novel Dietary supplement three times daily to prevent treat the mild neuropathy symptoms. In case of moderate to severe symptoms, the higher end of the dose range, 2 capsules three times daily may be required to control the symptoms of neuropathy initially; once the effective control of symptoms is achieved, the dosage can be gradually reduced to 1 capsule 2-3 times daily. For its potential preventive role against diabetic complications, 1 cap of this novel drug twice daily can be used as a routine supplement.

The structure of the raw materials used in the manufacture of the novel drug is shown in Fig.1 of the drawing. . The salient feature of the invention is to invent a novel Dietary supplement composition for preventing and treating diabetic neuropathy patients and a method of manufacturing the said Dietary supplement composition. The method of manufacturing the said Dietary supplement composition is disclosed.

RAW MATERIALS USED TO MANUFACTURING ALCRIN CAPSULES ARE DESCRIBED AS UNDER.

MANUFACTURING CONDITIONS DURING THE PROCESS OF MANUFACTURE OF THE CAPSULES ARE LISTED BELLOW

1. Ensure that the manufacturing area is free from unwanted materials as well as materials from the last batch.

2. Ensure that the equipments and the machinery to be used are clean, dry and bear status label.

3. Equipment and machines should be labeled properly for the product, batch no. & date prior to use.

4. Use hand gloves and nose masks at all times while handling the materials.

5. Take all the necessary precautions tominimize dusting at all stages.

6. All operations during filling, polishing & packing should be carried out in an AC and de-humidified areas

PH = 45% ± 5%

Temperature = 25°C ± 2°C

7. Blended material and filled capsules should be stored in double polythene-lined bags in drums with lids securely on and labeled accordingly.

8. Check that the locking of capsules is proper. 9. Alpha lipoic acid is light sensitive, hence exposure to light should be minimized

ADDITION OF PREVIOUS RECOVERABLE RESIDUE Details of residue:

5 1. Check the quantity of residue added

2. The recoverable residue should not be more than 3 months old

3. Not more than 5% of the residue should be added

4. Check the recoverable for physical appearance and absence of extraneous matter.

° 5. Counter check the weights of all recoverable residue to be used in the batches.

6. Send samples for QC for content, LOD, identification, and any other required parameters.

7. Recoveries should be added only at blending stage.

Each step in the process of manufacture of dietary supplement composition his given in detail. The manufacture of the product is explained in the following description.

Stage 1.0: Preparation of granulation solution:

Soak HPMC 15 caps in Isopropyl alcohol overnight, add Methylene chloride, stir it and use for coating of Alpha Lipoic acid [stage 2.]

Stage 2.0: Granulation of Alpha lipoic acid:

Weight Alpha lipoic acid and sift through 30 mesh S.S. serve. Load the sifted materials into a suitable mixer and mix for 5 minutes. Then add 22.200 kgs of HPMC solution (stage 1) to the mixer and wet it properly to get a dough like consistency. Pass this wet mass through 14 mesh and dry 0 the granules till all Methylene chloride is evaporated. Pass the granules tlπough 20 mesh. The granules to be collected in a double lines poUywogs and keep it in a fiber board drum.

5

Stage 3.0: Sifting and mixing:

Sift Inositol and Colloidal silicon dioxide through 40 mesh, mix in mass mixer for 30 minutes.

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Stage 4.0: Sifting & mixing:

Take chromium picolinate and grind it to a very fine powder using a motor and pestle or a small mixie. Mix 18.000 kgs of Dl-calcium phosphate in geometric progression with chromium picolinate and pass through 60 mesh. Sift remaining quantity of 25.000 kgs of Dicalcium Phosphate through 40 mesh sieve.

Stage 5.0 Blending:

Load Alpha lipoic acid granules [stage 2 ] into a blender. Then add Inositol and aerosol mixture [stage 3 ] and chromium picolinate and disclaim phosphate mixture [ stage 4 ], Magnesium stearate [sifted through 40 # ] and blend for 70 minutes.

Stage 6.0: Collection of granules:

Collect the granules in a clean having double polythene bags.

Total weight of the granules Theoretical weight of granules 265.000 kgs Percentage yield (N.L.T. 99.5%) Percentage Loss

Stage 7.0: Filling of capsules:

Calculation of blend to be filled: Weight of blend to be filled / capsule =530.0 mg Weight of blend to be filled 20 capsules =10.60 gms Weight of 20 empty capsules =

Weight of 20 filled capsules =10.60 gms + wt. of 20 empty Capsules

1. Area cleanliness

2. Equipment cleanliness

3. Identification / Colour / Quality of blend

4. Size / colour / quality of capsules

5. Temperature and humidity condition

6. Line Clearance

Stage 7.0: Filling of capsules \ contd..] PARAMETERS STANDARDS LIMIT TESTING FREQUENCY

Wt of20 filled capsules 10.60 gm + wt. of ±3% on Avg. wt. Every 30 minutes

20 empty caps Disintegration time NMT 15 minutes Every 2 hours

Room Temperature & RH NMT 25° C & 45° / RH Every 2 hours

Stage 7.1: Uniformity of weight:

Check individual weights of 20 capsules at every 2 hours. Time: Date: M/c.No.

Total weight of 20 capsule gm. Average wt of 1 capsule mg

5. Weight

% to- %

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

10. 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

15. invention.

Claims

1. A novel dietary supplement composition having the following ingredients

a). Alpha Lipoic Acid b). Inositol c). Elemental Chromium forming a synergistic composition

2. A novel dietary supplement composition having the following ingredients in their ideal proposion

a). Alpha Lipoic Acid 133 mg b). Inositol 250 mg c). Elemental Chromium 30 mg forming a synergistic composition

3. A novel process of manufacturing dietary supplement composition having the following steps.

a. Preparation of granulation solution as described, b. Granulation of alfa lipoic acid, c. Sifting and Mixing, d. Blending , e. Collection of granules in a clean drum having double polythene bag and f. Filling in capsules.

4. A novel process of manufacturing dietary supplement composition as claimed in claim 3 wherein prepration of granual solution consist in soaking HPMC 15 cps in Iopropyl alchohol over night, adding Methylene chloride, and strirring it before use for coating of alpha liponic acid

5. A novel process of manufacturing dietary supplement composition as claimed in claim 3 wherein granulation of alpha liponic acid is performed in the following manner.

weighing Alpha lipoic acid and sifting through 30 mesh S.S. sieve. loading the sifted materials into a suitable mixer and mix for 5 minutes, adding 22.200 kgs of HPMC solution (stage 1) to the mixer and wet it properly to get a dough like consistency, passing this wet mass through 14 mesh and dry the granules till all Methylene chloride is evaporated, passing the granules through 20 mesh, the granules being collected in a double lines poUywogs and keep it in a fiber board drum.

6. A novel process of manufacturing dietary supplement composition as claimed in claim 3 wherein Sift Inositol and Colloidal silicon dioxide through 40 mesh, mix in mass mixer for 30 minutes in a typical manufacture.

7. A novel process of manufacturing dietary supplement composition as claimed in claim 3 where in planting is carried out by Load Alpha lipoic acid granules [stage 2 ] into a blender, adding Inositol and aerosol mixture [stage 3 ] and chromium picolinate and disclaim phosphate mixture [ stage 4 ], Magnesium stearate [sifted through

40 # ] and blend for 70 minutes in a typical manufacture.

8. A novel process of manufacturing dietary supplement composition as claimed in claim 3 wherein collecting granules in a clean drum having double polythene bag and filling of capsules in a conventional manner and checldng the capsules regarding quality standard as defind in the description.

9. A novel dietary supplement composition as described in description.

10. A novel process of the manufacturing dietary supplement as described in description.