Title:  Chewable oral unit dosage

United States Patent:  6,589,551

Issued:  July 8, 2003

Inventors:  Jolliffe; Ian Gordon (Cottingham, GB)

Assignee:  Reckitt Benckiser Healthcare (UK) Limited (Slough, GB)

Appl. No.:  720349

Filed:  February 15, 2001

PCT Filed:  June 10, 1999

PCT NO:  PCT/GB99/01851

PCT PUB.NO.:  WO00/01372

PCT PUB. Date:  January 13, 2000

Abstract

An oral unit dosage comprising a substrate defining a plurality of discrete reservoirs each containing a liquid fill for release in the mouth.

SUMMARY OF THE INVENTION

According to the present invention there is provided a chewable oral unit dosage for releasing liquid in the mouth, comprising a soft ingestible substrate which includes a plurality of spatially-separated reservoirs, wherein each reservoir is adapted to retain liquid fills, preferably discrete liquid fills, and wherein the release of the liquid fills from the reservoirs occurs in a controlled manner when he unit dosage is chewed.

Preferably the oral unit dosage is a capsule, more preferably a gelatin capsule.

By controlled manner it is meant that, whether or not more than one liquid fill composition is used in the same capsule, the normal liquid fill volume is divided between a number of smaller reservoirs with the result that only a few reservoirs are burst in any one bite and the sudden burst of a large volume of liquid fill will be avoided.

The individual discrete reservoirs are non interconnecting and are spaced apart from one another.

Preferably in the oral unit dosages of the invention each reservoir has substantially the same volume.

Preferably the volume of each of the reservoirs in the oral unit dosages of the invention is not more than 0.5 ml, more preferably it is from 0.05 to 0.5 ml and most preferably from 0.1 to 0.35 ml.

Preferably the substrate of the oral unit dosages or the invention comprise from 2 to 30 reservoirs, more preferably from 5 to 20, and most preferably from 10 to 15.

Optionally the oral unit dosages of the invention may contain at least two different liquid fills in different reservoirs. The different liquid fills may separately contain components that would be incompatible if they were combined in a single liquid fill, for example two incompatible active materials or an active material and an incompatible excipient.

Examples of incompatible components include acids and bases; for example alginic acid and sodium bicarbonate, cetylpyridinium chloride and ascorbic acid, cimetidine and sodium bicarbonate, effervescent couples (e.g. citric acid and sodium bicarbonate), aspartame (a sweetener) and magnesium trisilicate (an antacid), cimetidine and vanilla (a flavouring agent), or benzocaine and cherry flavour.

It is possible in the oral unit dosages of the invention that the walls of the reservoirs are composed of a different material from the substrate in which they are embedded. However, it is preferred that the reservoir walls are composed of the same material as the substrate, i.e. the reservoirs are merely spaces in the substrate produced by the insertion of and/or including the liquid fill(s).

Thus, the oral unit dosages of the invention preferably consist essentially only of two components, the substrate and one or more liquid fills plus, optionally, a coating agent.

The substrate may comprise any film-forming material suitable for forming chewable capsules, for example suitably treated starch, cellulose or derivatives thereof or gelatin. Preferably the substrate comprises gelatin.

The substrate may further comprise agents to improve its handling or organoleptic properties, for example plasticisers (e.g. glycerine, sorbitol or propylene glycol, in amounts of up to 50%, more preferably 20-35%, by weight of the substrate); water (up to 50%, more preferably 30-40%, by weight of the substrate); preservatives (e.g. potassium sorbate or methyl, ethyl or propyl parabens); dyes; opacifiers; flavours; or additional drug substances.

The liquid fill will comprise either a solid active material that has been dissolved, solubilised, or dispersed (with suspending agents such as beeswax, hydrogenated caster oil or polyethylene glycol 4000), or a liquid active material; in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols, and surface active agents.

The liquid fill may optionally also comprise flavouring agents, sweeteners or powdery materials to improve the mouth feel of the fill once the reservoirs are broken open (e.g. bulk sweeteners such as sucrose or mannitol).

The selection of appropriate substrate materials plus excipients and fill materials will be obvious to one skilled in the art of chewable capsule production, and will depend largely upon the active material being delivered by the oral unit dosage of the invention.

It will be appreciated that, when the amount of fill material dosed into each reservoir is fairly low, care should be taken to ensure that the fill is not too viscous for accurate dosing. This will not be such a problem as in the production of single low volume capsules as the concentration of active agent will not need to be so high as in such capsules.

Suitable active materials for use in the oral unit dosages of the invention include any materials that may be formulated in a liquid fill, for example:

a) systemically acting agents, such as histamine H₂ receptor antagonists (e.g. ranitidine), proton pump inhibitors (e.g. omeprazole), prokinetic agents (e.g. metoclopramide), antidiarrhoeal agents (e.g. loperamide), laxatives (e.g. senna powder), non seroidal anti-inflammatory agents (e.g. naproxen, diclofenac, ibuprofen and aspirin) or decongestants (e.g. pseudoephedrine);

b) materials acting locally in the mouth, such as local antimicrobial agents (e.g. cetyl pyridinium chloride, hexyl resorcinol, triclosan), local anaesthetics (e.g. lignocaine hydrochloride, benzocaine) anti-inflammatory agents (e.g. aspirin, benzydamine, ketoprofen) steroids (e.g. hydrocortisone), topical antibiotics (e.g. tyrothricin, fusafungine, nystatin), decongestants (e.g. phenylephrine hydrochloride) or antihistamines (e.g. terfenadine);

c) materials acting locally in the throat or oesophagus, such as cough suppressants (e.g. dextromethorphan), expectorants (e.g. guiaphenesin), antacids (e.g. calcium carbonate, sodium bicarbonate), or soothing/coating agents (e.g. sodium alginate or dimethicone.

Suitable materials that may optionally be used to coat the oral unit dosages of the invention include cellulose derivatives such as hydroxy ethyl cellulose, hydroxy methyl cellulose or hydroxy propyl cellulose.

The oral unit dosages of the invention may be manufactured by any of the methods normally used for the production of chewable capsules having low fill volumes (taking into account the materials selected), with the special adaptation that the encapsulated dosages are not separated individually but are divided up so that each dosage comprises a plurality of discrete reservoirs. The method of manufacture may be further adapted so that each of the individual reservoirs has a volume of less than 0.5 ml and/or so that two or more different liquid fills are included in different reservoirs within the same oral unit dosage.

Commercial methods for producing chewable capsules include the plate process and the rotary die encapsulation process.

Example of the use of both the plate process and rotary die encapsulation machines are give in, for example, Soft Gelatin Capsules: A Solution To Many Tableting Problems by H. Seager in Pharmaceutical Technology, September 1985, 84-104; and Soft Gelatin Capsules by J. P. Stanley in Theory and Practice of Industrial Pharmacy Eds Lachman L, Lieberman H A, Konig J L, 405-420, 1976.

When the unit dosage is chewed, only a few reservoirs will burst yielding their liquid fill in any one bite with the result that a sudden burst of a large volume of liquid fill is avoided.

The invention will now be illustrated by reference to the following examples:

EXAMPLE 1

Liquid Fill                     mg Per Capsule
          Calcium Carbonate                    500
          Sodium Bicarbonate                   100
          Fractionated Coconut Oil             600
          Lecithin                              12
          Colloidal Silicon Dioxide              34
          Sorbitan Fatty Esters                 34
          Polysorbate 80 BP                     20
          Flavours/Colours/Sweeteners              80
                                       1380 mg (1.2 ml)
                Capsule Material           % by Weight
                Gelatin                        40
                Glycerin                       25
                Water                          35
                Mint Flavour                   qs
                Sweetener                      qs
                Colour                         qs
The oral unit dosages are prepared on a conventional rotary die encapsulation machine adapted to provide an individual fill volume of 0.1 ml; and further adapted so that the encapsulated reservoirs are not individually cut off but are divided up in blocks of 12 reservoirs i.e. each oral unit dosage comprises a single piece of gelatin defining twelve reservoirs each having a liquid fill of 0.1 ml.

The resultant chewable capsules deliver an antacid material to the throat and oesophagus without the "chalky" characteristics normally associated with conventional antacid tablets. The capsules are pleasant to chew and do not produce an unpleasant burst effect upon biting.

EXAMPLE 2

Liquid Fill 1                   mg per capsule
          Calcium carbonate                    100
          Sodium bicarbonate                   100
          Lecithin                              12
          Fractionated coconut oil             600
          Colloidal silicon dioxide              34
          Sorbitan fatty ester                  34
          Poly sorbate 80                       20
          Flavours/Colours/Sweeteners              80
                                       1380 mg (1.2 ml)
          Liquid Fill 2                   mg per capsule
          Alginic acid                         500
          Lecithin                              12
          Fractionated coconut oil             600
          Colloidal silicon dioxide              34
          Sorbitan fatty esters                 34
          Polysorbate 80                        20
          Flavours/Colours/Sweeteners              80
                                       1380 mg (1.2 ml)
 

Capsule Material
As example 1

The oral unit dosages are prepared as in Example 1 with the further adaptation that the two liquid fills are delivered separately to the capsules, such that each oral unit dosage comprises a single piece of gelatin defining twelve reservoirs each of 0.1 ml volume, six of the reservoirs containing liquid fills and six containing liquid fill 2.

Two capsules of Example 2 provide a full dose of alginic acid which will form a raft on contact with the stomach contents to treat heartburn, gastritis or dyspepsia.

When chewed the capsules of example 2 have a pleasant mouth feel and do not give a sudden unpleasant burst of fill material

Claim 1 of 20 Claims

What is claimed is:

1. A chewable oral unit dosage for releasing liquid in the mouth, said dosage comprising a soft ingestible substrate which comprises from 2 to 30 spatially-separated reservoirs, wherein each reservoir has a volume of not more than 0.5 ml and contains a liquid fill and wherein release of the liquid fill from the reservoirs occurs in a controlled manner when the unit dosage is chewed.

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