AU775850B2 - Improvements in tablet manufacture - Google Patents

Description

2717A

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant: Actual Inventor: Address for Service: Invention Title: Details of Associated Provisional Applications: spRee He4tcae t Lt a PAN PHARMACEUTICALS LIMIER D JOHN F. BRENNAN HODGKINSON OLD McINNES Patent Trade Mark Attorneys Level 3, 20 Alfred Street MILSONS POINT NSW 2061 IMPROVEMENTS IN TABLET

MANUFACTURE

No. PQ7114 filed on 26 April 2000 The following statement is a full description of this invention, including the best method of performing it known to me: IP Australia Documents received on :3 2 6 APR zuul Batch No: I f FIELD OF THE INVENTION The present invention relates to improvements in the manufacture of tablets, specifically effervescent tablets, and to such tablets manufactured by the process of this invention.

The invention involves using an improved formula that permits the manufacture and packaging of effervescent tablets under conditions less stringent than normal for this type of product. More specifically, this invention permits such tablets to be manufactured in a normal or ambient environment and also reduces the need to predry all ingredients to remove adsorbed water before blending them together.

S:i BACKGROUND Normal tablets are intended to be swallowed whole, with disintegration taking place in the body's digestive tracts, in which the temperature is approximately 38°C. By contrast, effervescent tablets are designed to be added to a glass of relatively cool water and allowed to dissolve. The resulting solution and suspended particles are then swallowed as a drink.

Effervescence is achieved by including one or more weak acids, for example citric or tartaric acid plus one or more effervescing alkalis, for example sodium bicarbonate, potassium bicarbonate or calcium carbonate in the formula. In the presence of small .i quantities of water, these ingredients react together, forming bubbles of carbon dioxide (the effervescent). At the same time more water is liberated which further promotes the reaction.

Depending on the nature of the active ingredients, these may either dissolve in the water or be suspended as fine particles in the solution.

Another feature of effervescent tablets is that no insoluble surface film or sediment should be present in the resulting solution. Further, the resulting solution should be palatable to the taste, requiring the presence of sweetening and flavouring agents.

tr When these requirements have been catered for, an effervescent tablet is generally much larger than a conventional tablet.

Using traditional formulae and processing methods, it has been necessary to pre-dry all ingredients to remove adsorbed water, then to granulate and compress the tablets in an environment in which the relative humidity is very low, for example less than Such conditions make compression of the tablet difficult to achieve, because a certain amount of moisture, for example 2.0 to is desirable to form a good tablet. This can be a significant manufacturing challenge.

Again it has traditionally often been necessary to individually wrap each effervescent i" tablet to protect it from atmospheric moisture during storage and distribution.

OBJECTS OF THE INVENTION It is an object of this invention to provide an effervescent tablet and a method or process of manufacturing which goes a long way towards overcoming or at least minimising the prior art problems or limitations outlined above.

o It is another object of this invention to provide an effervescent tablet, and a method or process of manufacturing the same, which is relatively stable under normal or ambient conditions.

It is a further object of this invention to provide an effervescent tablet formulation, where the manufacture thereof is possible in an environment wherein no special precautions have been taken to minimise the relative humidity of the air during the processing and packaging thereof.

It is yet another object of this invention to provide a tablet formulation that requires limited protection from atmospheric moisture during subsequent storage, or packaging and storage both before and after sale.

These and other objects of this invention will become more apparent from the following description.

SUMMARY OF THIS INVENTION According to one aspect of the invention there is provided an effervescent composition and especially an effervescent tablet composition or formulation, which includes one or more acids (eg citric acid or tartaric acid) and one or more effervescing alkalis (eg sodium bicarbonate, potassium bicarbonate or calcium carbonate) amongst the ingredients of the composition, wherein the acid component of the composition has been pre-coated with a protective layer of a polydimethylsiloxane which substantially minimises contact between the acid and atmospheric moisture until the composition is purposely mixed with water.

SAccording to another aspect of the invention there is provided a method of preparation of an effervescent composition, and especially an effervescent medicinal composition wherein the acid or other effervescing components are pre-coated with a polydimethylsiloxane before the coated component is further mixed with the other composition ingredients.

DETAILED DESCRIPTION Stability studies have demonstrated the effectiveness of the invention's formulation .i *and processing procedures and of the physical stability of tablets made in accordance with the invention. Accelerated stability studies have also been conducted at and 100% relative humidity for three months to assure that the seal between the cap and the body of the packaging protects the tablets therein from absorption of atmospheric moisture.

Preferably the pH of the polydimethylsiloxane is similar to that of the acid component, typically pH2-3. Preferably, the concentration of the polydimethylsiloxane varies in the range of about 0.05% to about 1.5% of the total weight of the composition.

.I The pre-coating of the effervescent acid component of the composition effectively precludes any reaction with the alkali component because of atmospheric moisture, even when the relative humidity of the air is more than about ten percent Further, compressed tablets manufactured according to the invention do not require any special protection from the atmosphere during subsequent storage, packaging and storage both before and after sale.

Preferably, according to the invention, the effervescent acid is loaded into the mixing bowl of a granulating machine fitted with a two-speed planetary mixing blade and separate horizontally mounted high speed chopper mixer. The polydimethylsiloxane :I is added and the conventional mixing blade is switched on, with high speed being 'jselected. Mixing continues until all of the acid has been coated with this material and a damp, solid mass has been formed. After this has been achieved, the chopper mixer of the machine is switched on and the mass is subjected to this treatment for about to 1.0 minutes, allowed by a further 2-5 minutes of high speed mixing by the planetary blade.

The mixture is then discharged from the granulating machine onto stainless steel trays in thin layers. These trays are then loaded into a drying oven pre-heated to and set at for about 18 hours to dry.

According to one embodiment using citric acid and using a Karl Fischer Titrator apparatus, the maximum water content of the dried, coated citric acid is 0.2% w/w.

This dried, coated citric acid is then loaded into a mixing machine where it is blended with the other ingredients of the composition, including the effervescing alkali, for about 3-5 minutes, then compressed into tablets.

An overview of the above described process is represented in the following flow chart.

FLOW CHART OF PROCESS Polvdimethvisiloxane 2- mnutesl

DRY

(18 hours n) c. tp.,z (mniq-iirp. r-ntpnt) Balance of Inaredients DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Vitamin B plus Milk Thistle Effervescent composition.

Ingredient Weight per table (mg) Citric Acid 1100 Calcium Carbonate 200 Polydimethylsiloxane Thiamine Mononitrate Calcium Pantothenate Pyridoxine HC1 Milk Thistle 42.900 Sodium Bicarbonate 800 Vitamin B12 0.060 Biotin 0.240 Inositol 0.240 Choline Bitartrate 0.050 S. Lactose 1406 Riboflavin 5-Phosphate Sodium 34.540 Nicotinamide Lime Powder Flavour Lemon Powder Flavour Sucralose Powder 9 Polyvinylpyrrolidone Polyethylene Glycol 6000 Fumaric Acid 72 Stability studies A batch of this product was manufactured as described herein. When packed, the vials were labelled with a storage requirement of "Store below 30 0

C".

Samples were taken for stability studies after two weeks and stored at 30 0 C (the labelled storage requirement) and 40 0 C, for accelerated study of the likely shelf life of the product.

These samples were tested on the initial date and at monthly intervals for the first three months and at three monthly intervals thereafter.

Samples were tested for Average Weight, Appearance, Effervescence Time, Hardness and Potency of five vitamins, namely Calcium Pantothenate, Nicotinamide, Pyridoxine Hydrochloride, Riboflavin and Thiamine Mononitrate.

The samples stored at 30'C showed no physical degradation and no abnormal loss of potency of any of the vitamins.

The samples stored at 40 0 C also showed no physical degradation and no abnormal loss of potency of any of the vitamins. It is accepted by the Australian Therapeutic Goods Administration, the division of the Australian Department of Health responsible for control of therapeutic goods throughout Australia, that stability studies at 40'C provide data that may be extrapolated by a factor of four in determining i' the likely shelf life of therapeutic goods.

Conclusion From the accelerated stability test results, it may be validly claimed that Vitamin B and Milk Thistle effervescent tablets made in accordance with this invention will *result in tablets that are stable both in terms of physical and potency aspects. Hence a label claim of a shelf life of two years may be anticipated.

From the stability test results for samples stored at 30°C, the labelled storage conditions, the indicated shelf life of two years is expected to be justifiable.

EXAMPLE 2 Vitamins B and C plus Guarana Effervescent composition.

Ingredient Weight per table (mg) Citric Acid 1000 Calcium Carbonate 100 Polydimethylsiloxane Thiamine Mononitrate 165 Pyridoxine HC1 11 Calcium Pantothenate 275 Vitamin B12 0.012 Biotin 0.180 Polyvinylpyrrolidone 98 Sodium Bicarbonate 800 Lactose 881 Sodium Ascorbate 603 Guarane 4:1 250 Riboflavin 5-Phosphate Sodium 16.5 Nicotinamide Sucrolose Powder 17 Pineapple Flavour Powder Polyethylene Glycol 6000 Fumaric Acid 49.31 Stability Studies A batch of this product was manufactured as described herein. When packed, the vials were labelled with a storage requirement of "Store below 30 0

C".

Samples were taken for stability studies after two weeks and stored at 30 0 C (the labelled storage requirement) and 40 0 C, for accelerated study of the likely shelf life of the product. These samples were tested on the initial date and at monthly intervals for the first three months and at three monthly intervals thereafter.

Samples were tested for Average Weight, Appearance, Effervescence Time, Hardness and Potency of four vitamins, namely Nicotinamide, Pyridoxine Hydrochloride, Thiamine Mononitrate and Vitamin C.

The samples stored at 30 0 C showed no physical degradation and no abnormal loss of potency of any of the vitamins.

The samples stored at 40°C also showed no physical degradation and no abnormal loss of potency of any of the vitamins. It is accepted by the Australian Therapeutic Goods Administration, the division of the Australian Department of Health responsible for control of therapeutic goods throughout Australia, that stability studies at 40'C provide data that may be extrapolated by a factor of four in determining the likely shelf life of therapeutic goods.

Conclusion From the accelerated stability test results, it may be validly claimed that Vitamins B and C plus Guarana effervescent tablets made in accordance with this invention will result in tablets that are stable both in terms of physical and potency aspects. Hence a label claim of a shelf life of two years may be anticipated.

From the stability test results for samples stored at 30 0 C, the labelled storage conditions, the indicated shelf life of two years is expected to be justifiable.

*ooo* o* ooo* EXAMPLE 3 Multivitamin plus Ginseng Effervescent composition.

Ingredient Weight per table (mg) Citric Acid 1100 Calcium Carbonate 100 Polydimethylsiloxane Magnesium Phosphate 47.5 d-alpha tocopheryl acid succinate 11 Thiamine Mononitrate 12.21 Calcium Pantothenate 8.80 Pyridoxine HC1 3.30 Polyvinylpyrrolidone Sodium Bicarbonate 800 Lactose 1525 Vitamin B12 0.0048 SBiotin 0.240 Folic Acid 0.240 Vitamin D3 Grade 100CWS.A 3.3 (equivalent to 330 International Units of Vitamin D3) Ferrous Sulphate 4.83 Copper Gluconate 3.57 Zinc Sulphate 2.75 .Magnesium Sulphate 1.54 Riboflavin 5-Phosphate Sodium 13.97 Nicotinamide 44 Ascorbic Acid 84 Ginseng Siberian 10:1 Sucrolose Powder Lime Flavour Powder Natural Lemon Flavour Powder Vanilla Flavour Powder Polyethylene Glycol 6000 Fumaric Acid 58.75 Stability Studies A batch of this product was manufactured as described herein. When packed, the vials were labelled with a storage requirement of "Store below 30 0

C".

Samples were taken for stability studies after five days and stored at 30 0 C (the labelled storage requirement) and 40 0 C, for accelerated study of the likely shelf life of the product. These samples were tested on the initial date and at monthly intervals for the first three months and at three monthly intervals thereafter.

Samples were tested for Average Weight, Appearance, Disintegration, and Potency of two vitamins, namely Nicotinamide and Vitamin C.

The samples stored at 30 0 C showed no physical degradation and no abnormal loss of potency of any of the vitamins.

The samples stored at 40 0 C also showed no physical degradation and no abnormal loss of potency of any of the vitamins. It is accepted by the Australian Therapeutic Goods Administration, the division of the Australian Department of Health 0i'" responsible for control of therapeutic goods throughout Australia, that stability studies at 40'C provide data that may be extrapolated by a factor of four in determining the likely shelf life of therapeutic goods.

Conclusion From the accelerated stability test results, it may be validly claimed that Multivitamin plus Ginseng effervescent tablets made in accordance with this invention will result in tablets that are stable both in terms of physical and potency aspects. Hence a label claim of a shelf life of two years may be anticipated.

From the stability test results for samples stored at 30*C, the labelled storage conditions, the indicated shelf life of two years is expected to be justifiable.

Stability Trials Packing System Samples from three separate batches of effervescent tablets were subjected to conditions of 100 per cent relative humidity and 40°C for three months to assure that the cap was effectively protecting the tablets within the vials. These conditions were achieved by completely immersing the filled and capped vials in a beaker of water and then placing the beaker in an oven at 40'C for twelve weeks.

At weekly intervals, all of the vials of tablets were removed from the water and opened to check for any entry of water and thus any degradation of the tablets.

The test results for these trials are as follows.

Conclusion The effervescent formulations tested demonstrate that the tablets are physically stable without individual wrapping to prevent effervescent occurring during storage.

Further, the packaging system of an aluminium tube and plastic cap used for effervescent tablets provides effective protection from moisture entering the tube and affecting the tablets.

The formulae and processing procedures according to the present invention permit the o* manufacture, storage and packaging of effervescent tablets in a manufacturing environment where the temperature but not the relative humidity of the air is controlled. As a result, the cost of both initial investment and operations in ooooo processing and packaging are significantly reduced. Still further savings in the costs of packaging are achievable because it is not necessary to individually wrap each such •tablet for protection.

Although exemplary embodiments of the present invention have been shown and ~described, it will be apparent to those having ordinary skill in the art that a number of changes, modifications or alterations to the invention described herein may be made, none of which depart from the spirit of the present invention. All such changes, modifications and alterations should therefore be seen as being within the scope of the present invention.

It should be appreciated that the present invention provides a substantial advance in the manufacture and storage of effervescent formulations, providing all of the hereindescribed advantages without incurring any relative disadvantages.

Claims (12)

1. An effervescent composition comprising at least one acid and at least one effervescing alkali amongst the ingredients of said composition wherein said at least one acid is pre-coated with a protective layer of a polydimethylsiloxane to substantially minimise the contact between said at least one acid and atmospheric moisture until said composition is purposely mixed with a suitable solvent.

2. The effervescent composition according to claim 1 wherein said at least one acid is citric acid or tartaric acid.

3. The effervescent composition according to claims 1 or 2 wherein said at least one effervescing alkali is sodium bicarbonate, potassium bicarbonate or calcium carbonate. 900

4. The effervescent composition according to any one of the preceding claims **wherein the polydimethylsiloxane used to pre-coat said at least one weak acid has a pH substantially similar to the pH of said at least one weak acid.

The effervescent composition according to claim 4 wherein the polydimethylsiloxane has a pH of about 2-3.

6. The effervescent composition according to any one of the preceding claims wherein the polydimethylsiloxane used to pre-coat said at least one weak acid has a concentration within the range of about 0.05% to 15% of the total weight of the composition.

7. The effervescent composition in accordance with any one of the preceding claims *wherein the effervescent composition is manufactured into tablet form.

8. The effervescent composition according to any one of the preceding claims wherein said effervescent composition is used for medicinal purposes.

9. An effervescent composition substantially as herein described and exemplified.

A method for preparing the effervescent composition as described in any one of claims 1-9 wherein said at least one acid and/or at least one other effervescing component of said composition is pre-coated with a polydimethylsiloxane before the pre-coated component(s) is further mixed with the remaining ingredients of said composition.

11. A method for preparing the effervescent composition substantially as herein described and exemplified.

12. An effervescent composition when prepared recording to the method as claimed in claim 10 or claim 11. Dated this 26 Ih day of April 2001 Sp~eta HfCOLe A d PAN UHtARtybkeEuTfALs LII~TvtED- BY: HODGKINSON OLD McINNES Patent Attorneys for the Applicant 0 000 00 0 0 0000 00 0 0 00 0 00