WO2004040992A1

WO2004040992A1 - Medicated comestibles

Info

Publication number: WO2004040992A1
Application number: PCT/GB2003/004823
Authority: WO
Inventors: Leigh Conyers
Original assignee: Ssl International Plc
Priority date: 2002-11-06
Filing date: 2003-11-06
Publication date: 2004-05-21
Also published as: AU2003283533A1; GB0225827D0; TW200500014A

Abstract

A chewable medicated comestible is made by mixing a pharmaceutically active ingredient, water and a substrate. The substrate has confectionery and binding properties and the mixing process produces a malleable solid confection which can be divided into discrete dosed units in the form of chewable tablets. The substrate may be a particular sugar.

Description

MEDICATED COMESTIBLES The present invention relates to chewable comestibles containing pharmaceutically active substances.

Conventional indigestion remedies comprising an antacid compound in powder form, such as calcium carbonate, are commonly supplied as hard chewable tablets whilst this represents a convenient means for delivering the active ingredient, the tablets have a disagreeable chalky taste and texture.

EP 0 075 443B describes chewable confectionary products containing inorganic antacid compounds. With these products the chalky taste and texture associated with the previously available antacid products can be effectively masked. One such product is sold under the Registered Trade Mark Remegel.

These products rely on the use of boiled sugar syrup in the formulation. However, this necessitates high temperatures in different stages of the manufacturing process. In practice, the active ingredient may be incorporated at temperatures in excess of 80°C.

Whilst the products of EP 0 075 443B can provide a satisfactory means of delivery of inorganic antacids they may not be suitable for other pharmaceutically active substances, particularly organic substances, which are temperature sensitive or which incorporate or are coated with heat sensitive materials such as wax or microencapsulated polyglycerides and which may undergo undesired chemical change during the high temperature formulation stages.

Also, the manufacturing process involves changes in the crystalline structure of the sugar during boiling, and again during the cooling of the boiled sugar. Since these crystalline changes are not always predictable there can be significant variation in the properties of the chewable product obtained. Accordingly, operation and control of the process can be complicated and expensive and may not be suitable for use with pharmaceutically active ingredients where stringent control of composition parameters and dosage is important.

An object of the present invention is to provide a manufacturing process for a chewable medicated comestible which can be readily economically performed in a controlled manner and is suitable for use with a wide range of pharmaceutically active ingredients.

According to the present invention there is provided a method for the manufacture of a chewable medicated comestible comprising mixing together water, a substrate comprising at least one particulate substance, and at least one pharmaceutically active ingredient, wherein the substrate has confectionary and binding properties whereby the mixing together of the substrate and the water produces a malleable solid confection which can be divided into discrete dosed units in the form of chewable tablets.

With this method, due to the use of a substrate with confectionary properties a product of acceptable taste can be obtained.

Also, due to reliance on the water/substrate mixing to provide binding the resulting malleable product can be made without requiring application of elevated temperatures. This facilitates ready performance of the process in a reliably consistent and carefully controlled manner and without the need to subject incorporated pharmaceutically active ingredients to destructive processing conditions. The process is therefore suitable for use with a wide range of pharmaceutically active ingredients and can be performed conveniently and economically.

The product produced with the method of the invention is malleable i.e. it has a pliable or plasticised gum consistency when chewed in the mouth rather than being of the nature of a hard brittle tablet. This provides an acceptable medium for delivery of the active ingredient particularly for administration of active ingredients to small children and those who have difficulty swallowing.

The metabolic decomposition of active ingredients once administered to a patient is a significant problem that medics and researchers are constantly presented with.

Classic administration routes e.g. intravenous injection and the alimentary canal, tend to accelerate the active ingredient's arrival at the liver where the majority of metabolic decomposition occurs.

Chewing the product of the present invention gives rise to the potential for administration of active ingredients via the buccal cavity of the mouth. Generally, active ingredients administered in this way enjoy slower metabolic decomposition by the body.

Advantageously therefore the present invention provides enhanced opportunities for administration of pharmaceutically active ingredients.

Moreover, due to the use of a water-based mixture the product can be formulated such that it can be consumed, and therefore the active ingredient can be administered, without need to take a drink at the same time.

The substrate may be any suitable pharmaceutically acceptable water soluble entity which does not chemically react with the said active ingredient(s).

Preferably the substrate comprises at least one particulate substance which provides or contributes to both the said confectionary properties and the said binding properties. This particulate substrate may be a natural sugar compound or modified starch or a synthetic sugar substitute or even a non-sugar synthetic polymer.

Preferably, this particulate substrate is a natural sugar, most preferably sucrose and/or glucose.

In order to provide the required physical binding properties, the particulate substrate preferably has a fme particle size, particularly a mean particle size ranging from 5 microns to 150 microns and most particularly a mean particle size of 10 microns to 80 microns.

A particularly preferred sugar is castor sugar or confectioner's sugar which is also known as icing sugar or powdered sugar. Where icing sugar is used it may be pure sugar or it may contain additives to prevent clumping such as starch.

With this preferred sugar the absorption of water by the substrate is facilitated such that binding to form a malleable consistency can occur without heating. This may be at room temperature or slight heating may be applied if necessary. Where heat is applied the temperature does not exceed 80°C, at least not when the active ingredient(s) is added. Also, a chewable product can be obtained with

- softer, more agreeable texture than a similar product made with boiled sugar syrup, yet which has a pleasant confection taste. The substrate constitutes from 30 % to 70 % by weight of the total product composition and preferably from 50 % to 60 % by weight of the total product composition.

It is not essential for the substrate to incorporate a particulate substance which provides both the confectionary and binding properties. Alternatively or additionally the substrate may comprise one or more separate or supplementary confectionary or binding modifier substances.

As a separate or additional binding modifier at least one whipping agent may be added to the substrate. Preferably the binding modifier may be added to the substrate as a foam which in particular is pre-blended with water and which in addition to at least one whipping agent may further comprise at least one starch component and/or at least one gelling agent.

The specific components of the binding modifier are dictated by the way in which the substrate is to be modified. Where the substrate requires lightening i.e. aerating, the whipping agent may be blended with water and the starch component to provide a material having a foam consistency which is then added to the substrate. Alternatively, where additional binding of the substrate is required a gelling agent may be blended into the binding modifier foam referred to above before it is added to the substrate.

A suitable whipping agent may include any of the following either alone or in combination milk protein, egg albumin or modified soya protein. Preferably the whipping agent is a commercially available milk protein.

The milk protein constitutes from 3 % to 10 % by weight of the binding modifier composition and preferably from 6 % to 7 % by weight of the binding modifier composition.

A suitable starch component may include any of the following either alone or in combination corn (or maize) starch, wheat starch or potato starch. Preferably the starch component is the corn starch.

The starch component constitutes from 5 % to 15 % by weight of the binding modifier composition and preferably from 10 % to 12 % by weight of the binding modifier composition.

A suitable gelling agent may include any of the following either alone or in combination gelatine, pectin, agar agar or gellan gum. Preferably the gelling agent is gelatine.

The gelling agent constitutes from 2 % to 15 % by weight of the binding modifier composition and preferably from 4 % to 5 % by weight of the binding modifier composition. Where pre-blended with water the water constitutes from 15 % to 30 % by weight of the binding modifier composition and preferably from 25 % to 30 % by weight of the binding modifier composition.

The binding modifier may comprise additional ingredients such as a sweetener in order to provide a pleasant confection taste. Suitable sweeteners which may be used alone or in combination may include any of the following sorbitol, fme sugar, Aspartame, Acesulfame K or Saccharin. Preferably the sweetener is sorbitol. The sweetener constitutes from 0 to 60 % by weight of the binding modifier composition and preferably from 45 % to 55 % by weight of the binding modifier composition.

The binding modifier constitutes from 5 % to 20 % by weight of the total product composition and preferably from 8 % to 12 % by weight of the total product composition. The at least one active ingredient may be any medicament or pharmaceutical compound. Suitable active ingredients which may be used alone or in combination, together with their utility, include; paracetamol (pain relief), antacids (indigestion), ibuprofen (pain relief, anti-inflammatory properties), diphenhydramine (antihistamine), meclozine (travel sickness), pseudoephedrine (decongestant), dexfromethorphan (cold relief), benzocaine (sore throat medication), lidocaine (anaesthetic), attapulgite (anti- diarrhoeal), loperamide (anti-diarrhoeal), mebendozole (parasite treatment), caffeine

(stimulant), cetylpyridium (mouth ulcer treatment), penicillin (anti-biotic), sodium citrate

(cystitis treatment), diclofenac (analgesic), anti-histamines (allergy relief and calming properties), domperidone (migraine treatment), herbal remedies, nicotine and vitamin supplements.

The said active ingredient(s) constitute from < 1 % to 40 % by weight of the total product composition dependent on the required therapeutic dosage.

The said active ingredient(s) may be incorporated into the composition as solid particles, a dispersion, a liquid or any other suitable physical form.

Preferably the active ingredient(s) is incorporated into the composition as solid particles which may be coated with a taste masking agent such as wax or microencapsulated polyglycerides in order to minimise the unpalatable flavour of the said active ingredient(s). Advantageously, the manufacturing process described herein enables the incorporation of the said coated actives as elevated temperatures need not be employed by the process described herein. The product of the present invention may also contain a supplementary binding agent to assist the binder in holding the components of the product together. Suitable agents, which may be used alone or in combination, include; polyvinylpyrrolidone, alginate, gum acacia, carrageenan. The polymer may constitute from 0 % to 10 % of the total product composition. In order to give the product acceptable mouth feel qualities the product may contain an edible fat. The fat may be of vegetable or animal origin or may even be a synthetic fat substitute. A suitable commercially available vegetable fat is Paramount C. The fat constitutes from 0 % to 6 % of the total product composition.

The product of the present invention may further contain additional ingredients such as colourings, flavourings, suspending agent, and bulking agents.

Suitable bulking agents include calcium carbonate, lactose, talcum powder, microcrystalline cellulose, maltodextrim and other modified starches and are included in the composition up to 50 % by weight of the total product composition.

The process of the present invention comprises the preparation of the chewable comestible product described herein may comprise a series of stages.

In one embodiment of the present invention the first stage of the process is the dry blending of an aliquot of the powdered substrate together with the said stabiliser. The blending occurs as the said substrate and stabiliser are passed through a sieve before entering a Z-blade mixer, such a mixer is well known to those skilled in the art. Sufficient water is then slowly added, with mixing, to this dry blend to form a granular mixture. It has been found that mixing the substrate mixture with water for about 5 minutes is sufficient time to furnish the desired granular mixture. The remainder of the powdered sugar is then added to the said granular mixture wherein the ensuing mixture is mixed for about a further 5 minutes. It is preferable to incorporate the powdered substrate in more than one aliquot due to its bulk density.

The components of the binding modifier i.e. a milk protein, water, a gelling agent, a starch component and a sweetener are mixed together separately before being added to the substrate mixture at room temperature i.e. 20-25°C. The resulting mixture is stirred at room temperature for about 5 minutes until a creamy mass ensues.

Thereafter, the colouring agents are added to the creamy mass and stirred for about 5 minutes or until a homogenous composition is observed. The mouth feel agent is then added to the mixture. Depending upon the physical nature of the mouth feel agent i.e. fat or oil, it may be necessary to melt the said agent to liquefy the said agent in order that when the said agent is added to the product mixture homogeneity is achieved.

The bulking agent calcium carbonate is then stirred into the product mixture. Ensuring the product mixture is at a temperature below 40°C and preferably below 30°C, the at least one active ingredient is stirred into the mixture.

Finally, the flavouring and any additional ingredients are added to the mixture and the resulting mixture is stirred for about a further 5 minutes.

In another embodiment of the present invention, the addition of water takes place after the addition of the binding modifier composition rather than in the middle of the powdered sugar mixing steps. That is, the binding modifier composition can be added to the dry blend of substrates and the mix stirred at room temperature for about 5 minutes. Sufficient water is then slowly added to this, with mixing, to form a smooth mixture. The remainder of the process is as described above.

Advantageously the process of the present invention is a one pot process. Furthermore the lower process temperature gives rise to a cost saving since steam and heat generation are not required.

It is necessary that the product mixture undergoes a so-called conditioning stage which facilitates the evaporation of water thereby providing a firm malleable product.

The product mixture is emptied into shallow trays and left until the desired firmness is achieved. The firmness of the product can be determined using suitable testing equipment such as a penetrometer. Generally, conditioning occurs at between 10 and

40°C in an atmosphere where the relative humidity is no more than 60. It has been found

that a conditioning time of about 24 hours is sufficient to furnish the desired physical characteristics of the product.

The elimination of the sugar boiling step and the reduced conditioning time give rise to more efficient and reliable manufacturing process.

The firmed product is removed from the trays and formed into discrete dosable units. For example chewable tablets can be cut from the conditioned product or the firmed product can be extruded and discrete tablets can be punched from the extruded material.

The invention will now be described by way of example only and with reference to the following examples which generically are in accordance with the following formulation:

Here the 'Binder' and 'Gelling agent' functions are combined together to create a 'Binding modifier composition', since the 'Gelling agent' is essentially part of the binding modifier.

Example 1

Example 2

Omeprazole is a substituted benzimidazole which is a gastric secretion inhibitor. Although it melts with decomposition at 155°C, it degrades rapidly in acidic media (sugars are mildly acidic).

This formulation results in chewable tablets. The tablets were analysed following BP analytical methods for the determination of Omeprazole (BP 2002). This demonstrated that there had been no decomposition or loss of Omeprazole. However, when a solution of 0.25% by weight Omeprazole in water containing 60% by weight dextrose monohydrate was heated at 80°C for one hour, analysis for Omeprazole showed severe degradation. Example 3

Promethazine hydrochloride is phenothiazine derivative which is used as an antiemetic and an antihistamine. It is subject to oxidation on prolonged exposure to air.

This formulation results in chewable tablets. The tablets were analysed following BP analytical methods for the determination of Promethazine hydrochloride (BP 2002). This demonstrated that there had been no decomposition or loss of Promethazine hydrochloride. However, when a solution of 0.625% Promethazine hydrochloride in water containing 60% dextrose monohydrate was heated at 80°C for one hour, analysis for Promethazine hydrochloride showed substantial degradation. Example 4

Vitamin C (ascorbic acid) is highly susceptible to oxidation at elevated temperatures.

This formulation results in chewable tablets. The tablets were analysed following BP analytical methods for the determination of Vitamin C (BP 2002). This demonstrated that there had been no decomposition or loss of Vitamin C. However, when a solution of 2.5% Vitamin C in water containing 60% dextrose monohydrate was heated at 80°C for one hour, analysis for Vitamin C showed substantial degradation.

It is of course to be understood that the present invention is not intended to be restricted to the above details which are described by way of example only. Thus, for example, vegetarian and 'sugar free' formulations can be used.

Claims

1. A method for the manufacture of a chewable medicated comestible comprising mixing together water, a substrate and at least one pharmaceutically active ingredient, wherein the substrate has confectionery and binding properties whereby the mixing together of the substrate and the water produces a malleable solid confection which can be divided into discrete dosed units in the form' of chewable tablets.

2. A method according to claim 1, wherein the substrate and water are heated such that the temperature does not exceed 80°C.

3. A method according to claim 1 or claim 2, wherein the substrate comprises a particulate substance.

4. A method according to claim 3, wherein the particulate substance provides or contributes to both the said confectionery properties and the said binding properties.

5. A method according to claim 3 or claim 4, wherein the particulate substance is a natural sugar compound, a synthetic sugar substitute or non-sugar synthetic polymer.

6. A method according to claim 5, wherein the natural sugar is sucrose and/or glucose.

7. A method according to claim 1, wherein the particulate substance is castor sugar or confectioners' sugar.

8. A method according to any of claim 3, wherein the particulate substance has a mean particle size in the range from 5 microns to 150 microns.

9. A method according to claim 7, wherein the particulate substance has a mean particle size in the range from 10 microns to 80 microns.

10. A method according to any preceding claim, wherein the substrate constitutes from 30% to 70% by weight of the total product composition.

11. A method according to claim 10, wherein the substrate constitutes from 50% to 60% by weight of the total product composition.

12. A method according to any preceding claim, wherein one or more separate or supplementary binding modifier substances is added to the comestible.

13. A method according to claim 12, wherein the binding modifier substance is selected from at least one whipping agent, at least one starch component and/or at least one gelling agent which is added to the substrate.

14. A method according to claim 12 or claim 13, wherein the binding modifier is added to the substrate as a foam which is pre-blended with water.

15. A method according to claim 14, wherein the water constitutes from 15% to 30% by weight of the binding modifier composition.

16. A method according to claim 15, wherein the water constitutes from 25% to 30% by weight of the binding modifier composition.

17. A method according to claim 13 or claim 14, wherein the binding modifier is a whipping agent which includes any of the following which may be used alone or in combination; milk protein, egg albumin or modified soya protein.

18. A method according to claim 17, wherein the milk protein constitutes from 3% to 10% by weight of the binding modifier.

19. A method according to claim 18, wherein the milk protein constitutes from 6% to 7% by weight of the binding modifier.

20. A method according to claim 13, wherein the starch component includes any of the following which may be used alone or in combination; corn (or maize) starch, wheat starch or potato starch.

21. A method according to claim 20, wherein the starch component constitutes from 5% to 15% by weight of the binding modifier composition.

22. A method according to claim 21, wherein the starch component constitutes from 10% to 12% by weight of the binding modifier composition.

23. A method according to claim 13, wherein suitable gelling agent include any of the following which may be used alone or in combination: gelatine, pectin, agar agar or gellan gum.

24. A method according to claim 23, wherein the gelling agent constitutes from 2% to 15% by weight of the binding modifier composition.

25. A method according to claim 24, wherein the gelling agent constitutes from 4% to 5% by weight of the binding modifier composition.

26. A method according to any of claims 12 to 25, wherein the binding modifier composition comprises at least one sweetener.

27. A method according to claim 26, wherein suitable sweeteners include any of the following which may be used alone or in combination; sorbitol, fine sugar, aspartame, acesulfame K or saccharin.

28. A method according to claim 26 or claim 27, wherein the sweetener constitutes from 0 to 60% by weight of the binding modifier composition.

29. A method according to claim 28, wherein the sweetener constitutes from 45% to 55% by weight of the binding modifier.

30. A method according to any preceding claim, wherein suitable active ingredients which may be used alone or in combination include any of the following; paracetamol (pain relief), antacids (indigestion), ibuprofen (pain relief, anti-inflammatory properties), diphenhydramine (antihistamine), meclozine (travel sickness), pseudoephedrine (decongestant), dextromethorphan (cold relief), benzocaine (sore throat medication), lidocaine (anaesthetic), attapulgite (anti-diarrhoeal), loperamide (anti-diarrhoeal), mebendozole (parasite treatment), caffeine (stimulant), cetylpyridium (mouth ulcer treatment), penicillin (anti-biotic), sodium citrate (cystitis treatment), diclofenac (analgesic), anti-histamines (allergy relief and calming properties), domperidone (migraine treatment), herbal remedies, nicotine and vitamin supplements.

31. A method according to any preceding claim, wherein the at least one active ingredient constitutes from < 1% to 40% by weight of the total product composition.

32. A method according to any preceding claim, wherein the active ingredient(s) is incorporated into the product composition as solid particles, a dispersion or a liquid.

33. A method according to claim 32, wherein the active ingredient(s) is incorporated into the product composition as solid particles wherein the said particles are coated with a taste masking agent.

34. A method according to claim 33, wherein the taste masking agent is a wax or micro encapsulated polyglycerides.

35. A method according to any preceding claim wherein a supplementary binding agent is added to the product composition.

36. A method according to claim 35, wherein the supplementary binding agent is selected from any of the following which may be used alone or in combination, polyvinyl pyrrolidone, alginate, gum acacia or carrageenan.

37. A method according to any preceding claim wherein an edible fat is incorporated into the product composition.

38. A method according to claim 37 wherein the edible fat is Paramount C.

39. A method according to any preceding claim wherein additional ingredients are incorporated into the product composition, these said ingredients are selected from colourings, flavourings, suspending agents and bulking agents.