GB2559449A - Hypoallergic drug delivery system - Google Patents

Abstract

A pharmaceutical composition comprising an active pharmaceutical agent and an excipient combination which acts as a diluent, disintegrant, anti-adherent or lubricant, wherein the pharmaceutical composition minimises adverse reactions to the components of the composition. In a preferred embodiment the excipient combination is rice starch and cellulose or a derivative thereof. Preferably the rice starch is pregelatinised or in the form of grains and the cellulose is crystalline or powdered. In some embodiments the composition is in the form of tablets or capsules. Preferably the compositions do not contain dyes, inks or colourings and are free from sulphites, benzoates and parabens. Carriers and drug delivery systems for the composition are also disclosed.

Description

(54) Title of the Invention: Hypoallergic drug delivery system

Abstract Title: Pharmaceutical compositions containing rice starch and cellulose.

(57) A pharmaceutical composition comprising an active pharmaceutical agent and an excipient combination which acts as a diluent, disintegrant, anti-adherent or lubricant, wherein the pharmaceutical composition minimises adverse reactions to the components of the composition. In a preferred embodiment the excipient combination is rice starch and cellulose or a derivative thereof. Preferably the rice starch is pregelatinised or in the form of grains and the cellulose is crystalline or powdered. In some embodiments the composition is in the form of tablets or capsules. Preferably the compositions do not contain dyes, inks or colourings and are free from sulphites, benzoates and parabens. Carriers and drug delivery systems for the composition are also disclosed.

At least one drawing originally filed was informal and the print reproduced here is taken from a later filed formal copy.

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open

1, The tapered rim prevents splitting and denting of the capsule

01 18

2/2

Front view

01 18

©Section covered by top cap ©Section exposed and visibie full shape of the traditional capsule

Figure 2

Hypoallergic drug delivery system

The present application relates to a drug delivery system designed to minimize adverse reactions and possible sensitization to the non-pharmacologically active components within the system. In particular, the application relates to a pharmaceutical composition which avoids the need for particular excipients, colours and inks associated with adverse reactions.

Pharmaceutical excipients are “substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form” (reference 1). In addition to transporting the active drug to the site in the body where the drug is intended to exert its action, excipients play an important part in the manufacturing process (e.g. compressibility into tablet form, ilowability into capsules, diluting agent). In addition, some excipients are used to aid the identification of a drug product (for example, using colour as an indicator). Some excipients are used simply to make the product taste and look better (for example, as described in references 2 to 6) and have no effect on the pharmacological activity of the drug.

Pharmaceutical ingredients (i.e. the “active drug”) can cause a range of established adverse reactions, rashes, gastrointestinal disturbance, utricaria, angioedema, and reactions specific to the drug itself (e.g. liver toxicity or bone marrow suppression). It is becoming increasingly clear that the excipients (e.g. the inactive pharmaceutical ingredients) can in themselves cause adverse drug reactions. Common excipient induced adverse drug reactions include hypersensitivity reactions (allergic), skin eruptions and gastrointestinal disturbance. The presence of colouring as an ingredient has also been associated with hyperactivity in children.

Allergies can develop to a range of substances, commonly foods, pollens, dust mite, animals and also drugs (as described in references 7 to 11). This can have a significant impact in quality of life and, where medication is involved, it can cause difficulties with prescribing choice. This latter problem is compounded by the use of commonly encountered allergens as excipients in many drugs, some of which are listed below. Examples include Roaccutane, a common medication used to treat acne, which is contraindicated in those with peanut or soya allergy (Roaccutane capsules contain soya oil). In addition, soya and peanut are common foods to which people often have an allergy (reference 12). Other examples of excipients for which allergies exist are listed below: Com, Carboxymethylcellulose, Chlorhexidine, Colour dyes, Carmine, Macragols, Benzoates and Mannitol.

Drugs can cause different types of allergic reactions termed immediate (Type I hypersensitivity reactions), psuedo allergic reactions and Type IV (delayed hypersensitiveity reactions). They can also sensitise an individual, resulting in an allergic reaction at a future date, such as potentially severe anaphylaxis.

Type I hypersensitivity reactions occur where the patient develops an antibody of the IgE type to an external non self component (e.g. food, pollen, drug) or excipient. These are known as allergens (i.e. the component that the individual is allergic to). These antibodies bind to special receptors (e.g. IgE Fc receptors) on the surface of mast cells and basophils (i.e. allergy specific white cells in the blood and tissues). When the patient is exposed to the allergen, it binds and cross links the IgE, and induces the release of chemicals (degranulation) from these white cells. These chemicals, which include histamine are usually released within minutes of exposure causing symptoms which range from a mild allergic rash (e.g. urticarial or hives) to lifethreatening anaphylaxis (references 13, 14). Excipients potentially causing IgE mediated reactions include peanut, soy, corn, chlorhexidine and Patent Blue V.

Pseudo allergic reactions occur where mast cells and or basophils (allergy specific white cells) are induced to degranulate in an IgE independent fashion (i.e. IgE antibodies are not involved) and this is thought to be due to a direct metabolic effect on these cells. An example of this is non steroidal anti inflammatory agents (e.g. voltarol, brufen, aspirin, diclofenac, etc.) and opiates. The reactions are clinically similar to Type I reactions and often indistinguishable (e.g. as described in references 15 to 17). Drug excipients potentially causing pseudo allergic reactions include sodium benzoate and benzyl benzoate.

Type IV delayed hypersensitivity reactions are IgE antibody independent reactions, which involve lymphocyte (a different form of blood white cell) and white cells called antigen presenting cells. Following exposure to the drug or chemical it usually takes one to two days before symptoms develop, usually in the form of a skin rash (reference 18). Excipients implicated in these reactions include Azo dyes and Propylene glycol.

Sensitising agents predispose patients to future allergic reactions. By exposure to this sensitising agent, the immune system is primed to react in an allergic or anaphylactic manner at a future date. An example of this is the use of cough mixtures containing pholcodeine sensitising patients to neuromuscular blocking drugs given post sensitisation prior to surgery, resulting in perioperative anaphylaxis (19, 20). Many drugs use colour distingusih the drug from others different drugs and also as a form of branding. The use of colourings in this way can result in future sensitisation to similar colourings used in other forms. A good example of this is Patent Blue V (often used as a tablet or capsule colouring), associated with severe allergic reactions during surgery for breast cancer. This dye is used to highlight lymph nodes during surgery and increasing numbers of anaphylaxis following administration of this dye have been reported in the literature (references 21 to 27).

Adverse excipient induced reactions have also been described in the literature, including lactose, which can cause cramps, bloating and diarrhoea in lactose intolerant individuals and hyperactivity in children due to colourings (reference 28).

The present invention seeks to ameliorate the problems associated with the prior art described above.

According to a first aspect, there is provided a pharmaceutical composition comprising an active pharmaceutical agent and an excipient which acts as a diluent, disintegrant, anti-adherant and/ or lubricant, wherein the pharmaceutical composition minimises adverse reactions to the components of the composition. Preferably, there is provided a pharmaceutical composition comprising an active pharmaceutical agent and an excipient combination tailored to minimize any adverse reactions not related to the active pharmaceutical agent (e.g. the active drug). Preferably, the pharmaceutical composition is a hypoallergenic (i.e. hypoallergic) composition. Preferably, the pharmaceutical composition consists of an active pharmaceutical agent and an excipient combination designed to minimize any adverse reactions not related to the pharmaceutical agent. The excipient combination will act as a diluent, disintegrant, antiadherent and/ or lubricant. The provision of such an excipient advantageously assists in the manufacturing process but is of such design to minimize excipient mediated adverse reactions.

In one embodiment, the composition is a hypoallergenic pharmaceutical composition designed to minimize any adverse reactions not related to the active pharmaceutical agent.

In one embodiment, the excipient comprises rice and cellulose. In another embodiment, the excipient comprises rice or cellulose. Preferably, the rice and cellulose are used in combination. In one embodiment, the excipient may comprise rice or cellulose in combination with another excipient.

It is preferred that the excipient comprises pregelatinised rice starch and/ or rice starch and/ or microcrystalline and/ or powdered cellulose starch. In one embodiment, the rice starch is provided in the form of rice starch grains. Preferably, the excipient comprises pregelatinised rice starch, rice starch and microcrystalline or powdered cellulose starch. In one embodiment, the rice starch is provided in the form of rice starch grains. In other embodiments, the composition may comprise other excipients. Preferably, the pregelatinised rice starch, rice starch and/ or microcrystalline and/ or powdered cellulose starch are used together. In another embodiment, the excipient comprises pregelatinised rice starch and/ or rice starch and/ or microcrystalline and/ or powdered cellulose starch, which may be combined with another excipient.

Preferably, the pharmaceutical composition is a tablet or capsule.

Preferably, the composition is free from sulphites, benzoates and/ or parabens.

Preferably, the composition is free from colourings, dyes and/ or ink.

Preferably, the composition is free from known sensitizers such as Patent Blue V and/ or chlorhexidine.

Preferably, the composition is free from common food allergens, used as excipients in drug formulations, including peanut, soya, gelatin, egg proteins, milk proteins, pine nut and sesame.

Preferably, the composition is free from ink and/ or colourings and/ or gelatin. Preferably, the composition further comprises plant polysaccharides and/ or their derivatives such as carrageenans and/ or modified forms of starch and/ or cellulose. It is preferable that the capsule comprises plant polysaccharides or their derivatives such as carrageenans and/ or modified forms of starch and/ or cellulose. In another embodiment, the tablet may comprise plant polysaccharides or their derivatives such as carrageenans and/ or modified forms of starch and /or cellulose.

According to a second aspect, there is provided a tablet comprising the pharmaceutical composition of the first aspect.

According to a third aspect, there is provided a capsule comprising the pharmaceutical composition of the first aspect.

Preferably, the tablet or capsule has a shape that assists in identification for the active drug and is easily administered and swallowed by the patient. It is preferred that the shape may be selected from one or more of the following: ridges, furrows, embossing and/ or tapering ends.

According to a fourth aspect, there is provided a method of producing the tablet of the second aspect or capsule of the third aspect having one or more of the following shape specific characterizations: (a) ridges; (b) furrows; (c) embossing; and/ or (d) tapering ends.

According to a fifth aspect, there is provided a method of improving drug stability and/ or shelf life of the tablet or capsule of the second or third aspect, the method involving the use of vacuumed blister packaging.

According to a sixth aspect, there is provided a method of improving the carriage and/ or compliance of the tablet or capsule of the second or third aspect, the method involving the use of individualized blister packaging.

According to a seventh aspect there is provided the pharmaceutical composition of the first aspect suitable for oral administration, aimed at minimising excipient induced adverse drug reactions.

According to an eighth aspect, there is provided a drug delivery system comprising the pharmaceutical composition of the first aspect. It is preferred that the composition includes at least one active pharmaceutical contained within a carrier system optimised for reduced propensity to induce related adverse drug reaction. The carrier system preferably includes an outer capsule which is preferably non-gelatin and instead comprises plant polysaccharides or their derivatives like carrageenans and/ or modified forms of starch and/ or cellulose (hydroxypropyl methylcellulose (HPMC)), which is ink and/ or colour free but has unique identifiers through shape and/ or texture. Preferably, the carrier system may be used with a capsule. In another embodiment, the carrier system may be used with a tablet.

Advantageously, the combination of pregelatinised rice starch with rice starch grains and/ or powdered cellulose in the appropriate proportions forms an effective excipient combination with low propensity to cause adverse drug rections, when contained within a hydroxypropyl methylcellulose capsule.

In one embodiment, the capsule is shaped through unique processing steps to provide a shape identifier rather than one based on colour or ink excipients. Advantageously, this allows the patient to identify a specific capsule by its shape, rather than by colour and/ or ink excipients. This is advantageous since this would avoid the patient potentially becoming sensitised to colour or ink excipients.

In another embodiment, the drug capsule is packaged using a vacuumed foil blister pack to improve drug stability and/ or shelf life.

Advantageously, the present invention relates to a method whereby a formulation of drug excipients is used in the manufacture of a range of drugs. Advantageously the method comprises the exclusion of the main excipients known to cause adverse drug reactions, such as being free from foods commonly associated with allergy (e.g. com, peanut, soy, gelatin or sesame) and free from inks and/ or dyes and/ or colourings and/ or chemicals such as macragols and benzoates (associated with adverse drug reactions and sensitisation reactions). Advantageously the composition may also be free from animal derived products such as gelatin. The exclusion of animal related components from the composition also has the advantage of removing any potential conflicts for religious, cultural or social reasons.

Thus, the composition of the invention advantageously provides a safe choice of drug for an increasing allergic population, and for those patients who may be anxious regarding excipient related adverse drug reactions, including potential sensitisation to drug excipients for which there is increasing awareness. The composition of the invention is advantageous for those patients who require drugs free from animal derived components.

Thus, the pharmaceutical composition of the present invention may be determined by the morbidities (pre existing disease such as allergy) and/ or social cultural factors (avoidance of animal derived products) of the user. Preferably, the pharmaceutical composition comprises cellulose capsules (hydroxypropyl methylcellulose (HPMC)). In another embodiment, the composition may comprise polysaccharides.

Capsules comprising HPMC have a number of advantages when compared with capsules comprising gelatin. For example, capsules comprising HPMC show rapid and comparable in vivo disintegration times when the patient is in the fasted state. HPMC capsules containing carrageenan as a gelling agent advantageously offers a practical alternative to gelatin capsules as an oral drug delivery carrier (reference 29). Regulations regarding the use of animal derived gelatin require the absence of bovine spongiform encephalopathy (BSE)/ transmissible spongiform encephalopathy (TSE) from the source material (reference 30). There are various religious, cultural and personal issues (references 31, 32) with gelatin, which is animal derived.

HPMC is not typically not associated with adverse drug reactions and there is only one case report in the literature regarding an allergic reaction to HPMC, which was present in Ocucoat and Xylocaine gel (rather than a drug capsule), this was administered intraocularly during cataract surgery (33).

Allergy to gelatin is observed more frequently in medicine with reactions described in the literature to, gelatin capsules (reference 34), gelatin found in vaccines (references 35 to 38) and intravenous colloid solution (reference 39). Gelatin capsules sticking to the oesophageal wall has also been reported.

Preferably, the capsule of the third aspect has no markings or colourings on the surface. Advantageously, this is to avoid the use of components that could potentially cause an adverse drug reaction or sensitize. For example, the provision of a capsule without colourings or markings may be advantageous to those patients who may suffer an allergic reaction though future exposure to the colouring or dye, for example, Patent Blue V. Since identification of the drug is important, in one embodiment, alternative methods of identification may be provided, including the provision of textured markings and/ or shapes as part of the capsule design.

In one embodiment, the manufacturing process uses pins which are dipped into the cellulose to form its shape. In one embodiment, the capsule comprises horizontal ridges to secure the capsule together in its assembled state. Typically, these ridges can be incorporated as a unique identifier in addition to parallel lines (incorporated into the dipping pins to add shape) and shapes added to the tip of the capsule.

In addition, it is preferred that the capsules are provided in blister packages with drug identification provided on the packaging, thus also providing an alternative to direct colouring or printing on the capsules.

Advantageously, the composition may be dye free, preservative free and/ or may contain a unique combination of pregelatinised rice starch, rice starch grains and/ or microcrystalline cellulose which forms an effective excipient combination with optimal performance and low association with adverse drug reactions.

Preferably, the present invention relates to a drug delivery system to deliver dosages of pharmaceuticals, medicines, vitamins, dietary supplements, etc. to an individual or animal with minimum adverse reactions (non active drug related).

The invention will now be described by way of example and with reference to the accompanying drawings, in which:

Figure 1 illustrates an embodiment of the invention showing modifications to the standard capsule shape which aid the closure and secure fitting of the capsule cap; and

Figure 2 illustrates an embodiment of the invention showing the core changes to the capsule design including more tapered end to the body of the capsule.

With reference to the drawings, there is provided a pharmaceutical composition comprising an active pharmaceutical and an excipient which acts as a diluent, disintegrant, anti-adherent and/ or lubricant to minimize non active drug related reactions.

Advantageously, the use of specific proportions of pregelatinised rice starch in combination with rice starch grains and microcrystalline cellulose forms an effective excipient combination. This combination demonstrates optimal performance combined with minimum excipient related adverse drug reactions.

Rice starch is highly compressible, although has poor flowability. Flowability is a very important part of manufacturing tablets and capsules, which involves several powder handling steps, including blending, transfer, storage, and feeding to a press or a dosator. The inability to achieve reliable powder flow during these steps can have a significant adverse effect on the manufacture and release of a product to market. Powder flow is influenced by particle size and shape, bulk density, surface area and several other material properties. The poor flowability of rice starch in this invention has been overcome by the use of spray dried rice starch in combination with partially pregelatinised rice starch. The pregelatised starch has improved flow and compression characteristics. In another embodiment both flow and compressibility of the formulation is improved with the addition of a specific proportion of microcrystalline cellulose. It is the individual and combined properties of these excipients that makes the mixture suitable for high throughput processing and avoids the need for other excipients.

The preferred proportion of excipients that may be used in accordance with the invention are set out below. The properties of the active pharmaceutical ingredient will influence the proportions used (see examples below) (Table 1)

Table 1. Excipient characteristics

Excipient	Concentration %	Fluidity	PH	Mean particle size	Angle of Repose
Rice starch	10-50	3.8	5.0-8.0	2-20 pm	>40°
Partially pregelitinised rice starch	10-50	18-23%	5.0-8.0	75-150 pm	40.7°
Microcrystalline cellulose	5-40	5-8.7%	5.0-7.5	20-180 pm	34.4°

Formulations:

The pharmaceutical composition of the present invention may be prepared by any known effective technique suitable for providing a pharmaceutical composition suitable for capsule drug delivery.

The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

There are no dyes or inks on the capsule and within the scope of this invention, all excipients often associated with adverse drug reactins are avoided, for example, note in particular there is no magnesium stearate or sodium stearyl fumarate, no sillicate derivatives, no calcium phosphate or hydrogenated oils (e.g. soybean oil) in these example formulations.

Example 1

Cold Relief

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Phenylephrine Hydrochloride	5mg
Paracetamol	500mg
Caffeine	25mg
Microcrystalline cellulose (E 460),	lOmg
Rice starch	3 5 mg
Pregelatinised rice starch	30mg

Example 2:

Ibuprofen 200mg

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Ibuprofen	40mg
Microcrystalline cellulose (E 460),	9 mg
Rice starch	27 mg
Pregelatinised rice starch	24 mg

Example 3:

Levothyroxine lOOmcg

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Levothyroxine	0.100 mg
Microcrystalline cellulose (E 460),	30 mg
Rice starch	100 mg
Pregelatinised rice starch	69.9 mg

Example 4:

Ramipril

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Ramipril	5mg
Microcrystalline cellulose (E 460),	20 mg
Rice starch	100 mg
Pregelatinised rice starch	50 mg

Example 5:

Simvastatin

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Simvastatin	20 mg
Microcrystalline cellulose (E 460),	10 mg
Rice starch	130 mg
Pregelatinised rice starch	40 mg

Example 6:

Isotretinoin 10 mg

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Isotretinoin	10 mg
Microcrystalline cellulose (E 460),	35 mg
Rice starch	150 mg
Pregelatinised rice starch	15 mg

Example 7:

Amlodipine

Capsule: Hydroxypropyl methylcellulose (HPMC), size 0, 1 or 2

Drug/excipient	Weight mg
Amlodipine	10 mg
Microcrystalline cellulose (E 460),	15 mg
Rice starch	75 mg
Pregelatinised rice starch	125 mg

In another embodiment, the capsule is shaped to aid tablet identification. In this embodiment, without the use of inks and/ or dyes in the formulation, drug identification is via the use of shape and/ or texture to the capsule design.

Capsules for the drug and health food industry typically have a characteristic and generally consistent shape and rely on colour and ink to identify the drug or product. Preferably, the tablet or capsule of the present invention is formed without additional colouring or ink and instead, the identifying characteristics are based on:

1) Changes to the shape of the capsule, e.g. in the form of (a) Ridges; and/ or (b) Furrows; and/ or (c) Embossing; and/ or (d) Tapering ends; and/ or

2) Packaging to the drug, with the identifiers (e.g. drug name and dose), among other important characteristics (e.g. expiry date) on the packaging.

Typically, during capsule manufacture, heated steel pins are dipped into an aqueous solution of thermogelling cellulose. It is the pin’s shape that moulds the form/shape of the capsule. Each capsule is typically made up of a capsule body and capsule cap, and these are determined by their corresponding pins. The method typically involves dipping the pins into the solution to cause the solution to solidify on the surface of the pins, removing the pins and drying the thermogelling solution on the surface of the pins to form capsule bodies and capsule caps. Pins are typically heated pre-dip and post-dip to facilitate solidification and counterilow air is applied to aid drying. Capsule parts may have a thick wall and a stiffening ring and are formed on undersized capsule-forming pins.

The invention preferably relates to methods and apparatus used in the manufacture of pharmaceutical capsules of variable shape and form, as opposed to the standard capsule shape.

U.S. 3,399,803 is directed to a hard-shell self-locking pharmaceutical capsule having a cap part and a body park the parts adapted for machine filling. U.S. 3,399,803 discloses mold pins having a uniform taper or candle-shape such as to avoid suction when the part is removed from the pin and to provide a wedging fit between the capsule cap and the capsule body. U.S. 3,399,803 also discloses the shaping of the cap and body to provide a semi-locked position and a locked position. A single groove in the cap and a matching single groove in the body provide a mechanical lock.

U.S. 3,508,678 and 3,664,495 disclose a capsule cap having an indent, in addition to a locking groove, which defines a prelock position by providing either an elastic friction fit with the capsule body (US 3,664,495) or a mechanical lock between the indent of the cap and the groove in the body (US 3,508,678).

U.S. 4,247,006 discloses a capsule body having a reduced diameter in the area, of its open end, and further the capsule cap and the capsule body each having an indentation to provide for a positive engagement of the body and the cap.

U.S. 4,758,149 is directed to a capsule forming pin having a cylindrical sidewall and a groove extending around the cylindrical sidewall, the groove having a non-angular cross-sectional profile, both the cylindrical sidewall and the groove having a smooth burnished-hardened surface. U.S. 4,758,149 discloses in Fig. 3A, item C and column 4, line 45, that a prior-art capsule cap pin for a 0 (zero) size capsule has a diameter at the cut-point of 0.2973-0.2978 inch (7.551-7.564 mm). The prior-art capsule body pin at the cut-point is 0.2848-0.2853 inch (7.234-7.247 mm).

There is provided a method and apparatus for manufacturing pharmaceutical capsules, each capsule typically consisting of a capsule body and a capsule cap. Preferably, the method of the present invention uses an aqueous solution of thermogelling cellulose into which heated capsule body pins and capsule cap pins act as moulds. Variation in the shape and contour of the pin will result in corresponding changes to the shape of the capsule. It is important that these modifications do not to interfere with removal of the capsule body or cap form the pin, joining of capsule body with capsule cap during later processing steps, movement of the capsule during later processing steps such as with high-speed filling machines where tolerances are tight, or handling of ability to swallow the capsule

For any given standard size of capsule (such as ”0, ”1”, 2, etc.), the size of the pin mould used in the prior art is a well-accepted with little variation in size. The combination of the standard pin mould diameter, accepted standards of wail thickness and shrinkage contribute to an overall dimensional standard for the outside diameter of a. capsule of a given size which can be accommodated without difficulty on high-speed filling machines where tolerances are tight.

Established modifications to the standard capsule shape are illustrated in Figure 1. These in particular aid the closure and secure fitting of the capsule cap.

Changes to the capsule body and / or cap (see figure 2 below) is the result of corresponding changes to their moulding pin. Small ridges can be added to the top cap or the lower body or both. This is in addition to the standard tapered rim and notches (figure 1). The number of ridges can vary adding a unique identifier. Figure 2 illustrates the core changes to the capsule design including more tapered end to the body of the capsule (dotted lines indicate standard capsule shape, solid lines show tapered shape and position of ridges). Figure 2 illustrates a 4 ridge example but this invention would be applicable to any number of ridges, greater of lesser than this. Similar ridges could be placed on the cap as an alternative or in addition to the body of the capsule.

In still a further embodiment, the capsule is sealed in a vacuum blister package to improve drug stability and shelf life and allow for drug name and dosage to be printed on the packaging.

Further embodiments include: individualised drug packaging, (one tablet or capsule per sealed container), vacuum sealed; addition of desiccant to remove moisture; and addition of anti oxidants.

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Publication

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US5014494 ί!:	27 Sep 1988	14 Mav 1991	Harrison Sherwood Medical	of preparation Method of sterilizing
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US 5145684 *	25 Jail 1991	8 Sep 1992	Sterling Drug inc	rapamycin and derivatives and prodrugs thereof Surface modified drug
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US2OO90O36862*	1 Aug 2007	5 Feb 2009	Healthcare, Inc. Owens -llinois Healthcare	bag Multilayer v> plastic
			Packaging	container and

Publication

			Inc.	method of storing lyophilized products
			Boston	PiftcKfi^c /Assembly
US20090314676 *		24 Dec 2009	Scientific Scimed, Inc,
				Package for
WO 1999003754A1 *	14 Jul 1998	28 J an 1999	American Horne Products Corporation	storing a product in a controlled atmosphere and method of making it

Claims (19)

1. A pharmaceutical composition comprising an active pharmaceutical and an excipient which acts as a diluent, disintegrant, anti-adherent and/ or lubricant, wherein the pharmaceutical composition minimises adverse reactions to the components of the composition.

2. The pharmaceutical composition of claim 1, wherein the excipient comprises rice and/ or cellulose.

3. The pharmaceutical composition of claim 1 or 2, wherein the excipient comprises pregelatinised rice starch and/ or rice starch grains and/ or microcrystalline or powdered cellulose starch.

4. The pharmaceutical composition of any preceding claim, in the form of a tablet or capsule.

5. The pharmaceutical composition of any preceding claim wherein the composition is free from sulphites, benzoates and/ or parabens.

6. The pharmaceutical composition of any preceding claim wherein the composition is free from colourings, dyes and/ or ink.

7. The pharmaceutical composition of any preceding claim wherein the composition is free from known allergic sensitizers such as Patent Blue V and/ or chlorhexidine.

8. The pharmaceutical composition of any preceding claim wherein the composition is free from common food allergens, used as excipients in drug formulations, including peanut, soya, gelatin, egg proteins, milk proteins, pine nut and sesame.

9. The pharmaceutical composition of any preceding claim wherein the composition is free from ink and/ or colourings and/ or gelatin.

10. The pharmaceutical composition of any preceding claim comprising plant polysaccharides or their derivatives such as carrageenans and/ or modified forms of starch and/ or cellulose.

11. A tablet comprising the pharmaceutical composition of any preceding claim.

12. A capsule comprising the pharmaceutical composition of any one of claims 1 to 10.

13. The tablet of claim 11 or capsule of claim 12, wherein the tablet or capsule has a shape that assists in administration to a patient.

14. A method of producing the tablet of claim 11 or capsule of claim 12 having one or more of the following shape specific characterizations: (a) ridges; (b) furrows; (c) embossing; (d) tapering ends.

15. A method of improving drug stability and/ or shelf life of the tablet or capsule of any one of claims 11 to 13, the method involving the use of vacuumed blister packaging.

16. A method of improving the carriage and compliance of the tablet or capsule of any one of claims 11 to 13, the method involving the use of individualized capsule packaging.

17. A carrier system for the pharmaceutical composition of any one of claims 1 to 10 suitable for oral administration, wherein the system minimises excipient induced adverse drug, including allergic reactions.

18. A drug delivery system comprising the pharmaceutical composition of any one of claims 1 to 10.

19. A hypoallergenic pharmaceutical composition comprising an active pharmaceutical and an excipient which acts as a diluent, disintegrant, anti-adherant and/ or lubricant.

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Application No: GB1717991.2 Examiner: Miss Anna Crosby