GB2314024A - A novel suppository - Google Patents

Abstract

The present invention relates to the provision of novel suppositories of improved shape. Particular embodiments of the invention provide suppositories which are shaped so as to ease insertion into such an orifice and/or to increase retention in the orifice.

Description

A NOVEL SUPPOSITORY The present invention relates to novel suppositories, and to methods of administering pharmaceutically active compounds using the novel suppositories.

Suppositories are widely used solid formulations for administering pharmaceutically active agents via the rectum, vagina and more rarely the urethra. They may be used to administer drugs locally or systemically. Local treatment using suppositories includes the administration of drugs such as emollients, astringents, antibacterials, hormones, steroids and local anaesthetics. Rectal suppositories are frequently used for the local treatment of constipation and haemorrhoids. Such suppositories are usually designed to deliver their effect within about half an hour but at least within about four hours.

Suppositories may also be used to administer drugs such as analgesics, anti-emetics, antispasmolytics, sedatives, tranquillisers, antibacterials and NSAIDS for systemic treatment. This mode of administration is desirable where oral medication would not be retained or absorbed properly. Typically suppositories are used to administer drugs to patients that are unconscious, are suffering from severe vomiting or paralytic ileus. The use of suppositories in such situations is less invasive than alternative methods such as intravenous administration.

Suppositories are also useful in the administration of drugs which are not suitable for oral administration. This is particularly desirable for drugs which cause gastrointestinal side effects when taken orally, drugs which are not sufficiently stable at the pH of the gastrointestinal tract, drugs which are susceptible to the enzymes present in the gastrointestinal tract and drugs which are readily degraded in the liver after absorption.

The use of suppositories may also be desirable to administer drugs with particularly unpleasant taste.

Suppositories are typically formed from a base which melts or dissolves at body temperature either to provide direct local relief or to release a drug or other material which is to be administered.

Rectal suppositories are typically 'bullet' or 'torpedo' shaped and weigh from ig to 4g.

Suppositories are most commonly formed by mixing the therapeutic agent to be administered (if one is to be included in the suppository) and any further excipients into the molten base. The mixture is then cooled in a 'bullet' or 'torpedo' shaped mould to form the suppository.

Rectal suppositories can also be prepared from aqueous systems although this is less common. Such suppositories are prepared by heating water with a gelling system. If a therapeutic agent is to be included in the suppository it is then added to the mixture together with any further excipients. The mixture is then poured into a mould and allowed to solidify. Alternatively, any excipients can be added to the water prior to the gelling agent, this may be preferred when manufacturing the suppositories on a large scale.

Some suppositories may require storage at low temperatures in order to prevent distortion of their shape due to melting of the base from which they are formed, however most can be stored at room temperature for adequate periods of time without any deterioration. This is particularly so for suppositories which contain preservative additives.

Vaginal suppositories, also referred to as pessaries, may be prepared by the methods described above. Alternatively they may be prepared by compressing the drug together with excipients into a suitable tablet shape. This type of suppository disintegrates into the body fluids rather than melts. They are often globular or oviform in shape and typically weigh about 3-5g. Drugs for vaginal administration may also be prepared within soft gelatin capsules.

The shape of rectal/vaginal suppositories has changed little since the 'torpedo shape' was introduced by Henry S Wellcome over a century ago. [Wellcome HS, An Improved Shape For Suppositories And Bougies, Proceedings of the 41st annual meeting of the American Pharmaceutical Assn. Philadelphia, The American Pharm. Assn. 1893 pp 103104]. This shape consists of an apex (pointed end) tapering to a blunt base. Although suppositories vary a little in their dimensions the basic 'torpedo' shape is still used.

Despite their wide use, suppositories of this shape have some disadvantages. Insertion of the suppository into the anal passage is not easy and the suppository is often expelled from the rectum by the action of the anal sphincters. This causes obvious discomfort and distress to the user as well as hindering the intended treatment. GB 2252043 describes shaped suppositories which contain crenellated surfaces to increase their surface area and so improve the delivery of drugs from them, however it does not address the problems described above, namely ease of use and retention in the body.

A further disadvantage with the current shape of suppositories is that in order to fully insert the suppository into the rectum and avoid subsequent expulsion it is often necessary for the user to insert a finger into the anal passage. This adds to the discomfort and distress of many users and may even deter them from administering their treatment regularly. The use of suppositories is in any case aesthetically unpleasant and these disadvantages further discourages their use.

The majority of suppository users self-administer their treatment. Generally they are supplied with suppositories without being given detailed instructions on how they should be inserted, in particular they are not given advice on the direction in which the suppository should be inserted. It appears that most people using a suppository insert it apex first. This is a logical approach because the apex is the pointed end. Also, suppositories are usually manufactured in torpedo shaped moulds with the apex at the base of the mould. Filling equipment is used to dose the base into the moulds and as the material cools it may contract slightly at the top of the moulds. This results in the formation of a torpedo shaped suppository with a smooth moulded apex and a roughly finished base. This further encourages a user provided with no detailed instructions on how to insert the suppository to insert it apex first, i.e. to insert it via the smooth, moulded apex rather than with the rough unfinished blunt end first.

A study by Abd-El-Maeboud et al shows that only few users insert a 'torpedo' shaped suppository by the blunt end first [K.H. Ab-El-Maeboud, T. El-Naggar, E.M.M. El Hawi, S.A.R. Mahmoud and S. Abd-El-Hay, Rectal Suppository: common-sense and the mode of insertion, The Lancet, Vol. 28, Sept. 28, 1991, pp 798-800]. In this article he suggests insertion via the blunt end as an alternative but there is no indication that the practice of user or indeed practitioners has changed in light of this teaching.

There is therefore a need for a suppository which is easy to insert; which avoids easy expulsion from the orifice in which it is to be used and retention of the suppository or a suppository with a combination of these features.

The present invention provides novel suppositories of improved shape which overcome one of the disadvantages of previous designs. Inter alia the invention provides suppositories having a shape which facilitates their insertion into the rectum via the anus and thereby increases the ease of use; suppositories which in use have improved retention in the orifice and/or suppositories which are suitable for insertion into an orifice of a human or animal body via either end of the suppository without affecting their ease of use. The suppositories of the invention may have a combination of these advantageous features.

The present invention provides a suppository for insertion into an orifice of a human or animal body comprising an elongated body having a proximal end adapted to be inserted into the orifice, a distal end adapted to lie within the orifice after insertion and a central portion between the ends, the surface of the central portion being provided with one or more spiral or annular projections and/or depressions.

Preferred embodiments of the invention are those in which the body is a non-compressed body, e.g. a moulded body or a gel-encapsulated body. The suppository is preferably solid.

The suppositories of the present invention are preferably suppositories suitable for manual insertion into an orifice of the human or animal body and they are more preferably suitable for insertion into the rectal passage of said animal or human body.

Preferred embodiments of the invention are those which are suitable for full insertion into the rectum of the human or animal body. Thus rectal suppositories are preferred embodiments of the invention.

The proximal end of the suppository is preferably adapted to enter the orifice by comprising tapered sides which form an apex. The distal end of the suppository is adapted to lie within the orifice after insertion and will therefore not comprise any projections which would restrict its entry into said orifice. It may suitably be curved. In preferred embodiments the distal end tapers out into a bulb shape, providing a surface on which the anal sphincters may act to propel the suppository further into the rectum. This increases the ease of insertion of the suppository into the rectum and also improves the body's ability to retain the suppository in use.

The projections are preferably arranged along the length of the body of the suppository.

The projections may be formed by ridges or by smaller shapes, e.g. by pimples arranged around the body of the suppository. The suppository preferably comprises a central portion having one or more tapered ridge portions. The suppository preferably comprises two or three tapered ridge portions disposed along the length of the suppository. These preferably taper out from the proximal end of the suppository towards the distal end. In preferred embodiments the ridge portions taper sharply towards the distal end of the suppository and more gradually towards the proximal end. Particular embodiments of this aspect of the present invention comprises two tapered ridge portions spaced approximately equidistant from the ends of the length of the suppository.

The tapered ridge portions of the suppository preferably provide a surface on which the anal sphincter may act to propel the suppository further into the rectum. For example, when the tapered ridge portions taper out from the proximal end towards the distal end they provide a bulbous area on which the anal sphincters can act as described above in the first aspect of the invention.

Particularly preferred embodiments of this aspect of the invention comprise tapered ridge portions and a distal end which all comprise a surface on which the anal sphincters can act to propel the suppository into the rectum. The anal sphincters may act on these surfaces, further increasing the ease of insertion of the suppository into the rectum and also increasing its retention.

The insertion of such a suppository is so improved that it decreases the need (if any) for a user to insert his finger into the anal canal when using it. This is clearly advantageous both in improving the experience of using the suppository and in decreasing the likelihood that the user will be deterred from continuing their treatment.

Depressions such as constrictions may be used instead of projections as is exemplified in Example 4. A single constriction is preferred and it is preferably located at the centre of the suppository. Such depressions provide surfaces on which the sphincter muscles can act in a similar way to that described above.

Preferred embodiments of the invention provide suppositories comprising both projections and depressions, preferably associated with each other. The combined projection and depression provides a superior surface on which the sphincter muscles can grip and propel the suppository into the orifice, thus facilitating both insertion and retention of suppository within the orifice. The ridge portions described above may suitably be shaped to provide both projections and depressions, i.e. part of the ridge may be raised while a further part is depressed.

The suppositories of the invention may suitably have identical ends so that the suppository may inserted via either end without affecting its effectiveness.

The suppositories of the invention are suitable for use to provide a local or systemic effect. Preferred embodiments being suitable for the local treatment of haemorrhoids.

The suppositories of the invention may be prepared from any suitable base material, such as theobroma oil, fats and wax mixtures with theobroma oil, glycerinated gelatins, hydrogenated vegetable oils, fatty acids of polyethylene glycol and mixtures of different weight polyethylene glycols. The particular base used in a suppository will depend on the active ingredient to be incorporated into it and the desired rate and mode of release of the drug. For example, theobroma oil melts quickly at body temperature and is a good base for alleviating irritation e.g. in the treatment of haemorrhoids. However, because it forms a non-absorbable resin it is rarely used in the formation of vaginal suppositories.

Glycerinated gelatins may also be used in rectal suppositories, however some reports have indicated that they have a slow dissolution rate and are not desirable. Polyethylene glycols are the preferred vehicles for administering antiseptics.

Suppositories for the treatment of haemorrhoids preferably include active constituents such as astringents, vasoconstrictors, topical anti-inflammatories e.g. steroids such as hydrocortisone, and/or local anaesthetics which provide symptomatic relief and/or amelioration of the pain accompanying defecation. Examples of astringents which may be included in the suppositories of the invention include zinc oxide and calamine.

Examples of vasoconstrictors which may be included include phenylephrine, ephedrine sulphate, ephedrine and ephedrine hydrochloride and examples of local anaesthetics include benzocaine, dibucaine, lidocaine, pramoxine, amethocaine and their hydrochloride salts.

Rectal suppositories may suitably be formed by conventional methods e.g. by mixing the therapeutic agent to be administered (if one is to be included in the suppository) and any further excipients (e.g. preservatives such as methyl and propylhydroxybenzoates and/or anticoagulants such as sodium metabisulphite) into the molten base. The mixture is then cooled in a bullet shaped mould to form the suppository.

A pre-formed suppository mould may suitably be prepared in two halves by thermoforming a flat sheet of thermoplastic material such as PVC (polyvinylchloride), PVC/PVdC (polyvinylchloridelpolyvinyldichloride) or PANIPE (polyacrylonitrile/polyethylene) into the desired shape. The two halves formed in this are then sealed together leaving the top edge unsealed and providing a complete mould of the desired shaped cavity. The base material, e.g. gelatin or theobroma oil is poured into the mould and the top edge of the mould heat sealed to form a blister around the base material.

If additives or active therapeutic ingredients are to be included in the suppository they may be added to the base material prior to pouring it into the mould. As the base sets the suppository is formed surrounded by a primary packaging material. This method is suitable for the preparation of large numbers of suppositories which can be further packaged before distribution.

Alternatively the suppository of the invention may suitably be prepared by melting a wax base to a temperature just above its solidification point and then pouring it into a mould such as that described above. The filled mould is allowed to cool and solidify to form the suppository. If additives or active therapeutic ingredients are to be included in the suppository they may suitably be added to the molten wax with agitation, to provide a homogenous mixture which is poured into the mould and allowed to cool and solidify as described above.

If desired additives such as melting point regulators and surfactants (e.g. sodium lauryl sulphate) may be added to the molten wax. Preservatives and antioxidants such as those described above may also be added, however as wax is less susceptible to microbial spoilage than bases these additives are less important in the preparation of wax suppositories.

Rectal suppositories may also be prepared from aqueous systems, although this is less common, by heating water with a gelling system. If a therapeutic agent is to be included in the suppository it is then added to the mixture together with any further excipients.

The mixture is then poured into a mould and allowed to solidify. Alternatively, any excipients can be added to the water prior to the gelling agent, this may be preferred when manufacturing the suppositories on a large scale.

The amount of therapeutic agent included in suppository will depend on the dose to be administered, the type of release required and the vehicle used. If the therapeutic agent is not soluble in the base it may preferably be ground into a fine powder prior to being homogeneously dispersed in the base. Ionised or unionised drugs may be selected for use in the suppository depending on the base used, the nature of the drug and the location of its desired effect.

The suppositories of the present invention may be designed to be suitable for medical or veterinary use. They may also be modified for use on children e.g. by reducing their size. The suppositories may be inserted into the orifice of the human or animal body directly by the user or they may be inserted using an applicator e.g. an applicator such as that described in US 3433225. However, embodiments which are easy to insert dispense with the need for such an application.

The present invention also provides methods for the administration of a material to a human or animal body comprising the use of a suppository as described above. The material may suitably be a pharmaceutical or a prophylactic material or any other material which provides at least some relief to the body. The methods are suitable for treating conditions in which the application of a chemical has some beneficial effect on the human or animal concerned.

The invention further provides methods for the alleviation of a condition of a human or animal body comprising the insertion of a suppository as described above into an orifice of a human or animal body. This alleviation includes partial as well as total relief from pain or discomfort as well as the total or partial treatment of the cause of such pain or discomfort. Alleviation may suitably be provided by the material from which the suppository is manufactured. These methods are particularly suitable for the treatment of haemorrhoids.

Preferred embodiments of this aspect of the invention are suppositories suitable for the treatment of haemorrhoids by the application of a soothing material to the area to be treated or the application of analgesics or anti-inflammatory compounds.

The present invention will now be exemplified with reference to the following Examples and Figures, by way of illustration only.

FIGURES Figure 1. is an elevated view of a suppository according to the invention.

Figure 2. is a cross section of a suppository according to the invention taken along plane A-A'.

Figure 3. is a cross section of a suppository according to the invention taken along plane B-B'.

Figure 4. is an elevated view of a further suppository according to the invention.

Figure 5. is a cross section of the further suppository taken along plane A-A'.

EXAMPLES EXAMPLE 1: METHOD FOR THE PREPARATION OF A GELATIN BASED SUPPOSITORY ACCORDING TO THE INVENTION A suppository as illustrated in Figure 1 is prepared using a pre-formed suppository mould. The mould is prepared in two halves by thermoforming a flat sheet of thermoplastic PVC into the desired shape. Two halves of the mould formed in this way are sealed together leaving the top edge unsealed and providing a complete mould having a cavity of the desired shaped.

The gelatin base is poured into the mould and the top edge of the mould heat sealed to form a blister around the gelatin. As the gelatin sets the suppository is formed surrounded by a primary packaging material. This method is suitable for the preparation of large numbers of suppositories which can be further packaged before distribution.

The suppository formed by this method has a proximal end (1), a central portion (2) having two tapered ridge portions (3) which are disposed along the length of the suppository and a distal end (4). The proximal end (1) has tapered sides which form an apex, this increases the ease of insertion of the suppository into the rectum. The distal end (4) tapers out into a bulb shape, providing a surface on which the anal sphincters may act to propel the suppository further into the rectum, increasing the ease of insertion of the suppository into the rectum. The shape of the distal end (4) also improves the body's ability to retain the suppository in use because the anal sphincters continue to act on it pushing the suppository further into the rectum and preventing it from being expelled.

The two tapered ridge portions (3) taper out from the proximal end (1) in the direction of the distal end (4) and are spaced approximately equidistant from the ends of the suppository. These portions provide further bulbous surfaces on which the anal sphincters may act to propel the suppository further into the rectum. They further increase the ease of insertion of the suppository into the rectum and further improve the body's ability to retain the suppository after insertion.

The insertion of the suppository into the rectum is improved to the extent that many users will not need to insert a finger into the anal canal when using it.

EXAMPLE 2: PREPARATION OF A SUPPOSITORY FOR THE DELIVERY OF HYDROCORTISONE A suppository containing hydrocortisone for the treatment of haemorrhoids is prepared by a method similar to that described above in Example 1. A pre-formed suppository mould is prepared by the method described above. Hydrocortisone is added to the gelatin base together with methyl and propylhydroxy benzoates as preservatives and the anticoagulant sodium metabisulphite. The mixture is then poured into the mould and the top edge of that mould heat sealed to form a blister around the mixture which sets inside the mould. In this way a suppository containing hydrocortisone is formed surrounded by a primary packaging material.

The suppository formed is of the same shape as that formed according to the method of Example 1 and has the advantages described above.

EXAMPLE 3: PREPARATION OF A WAX BASED SUPPOSITORY ACCORDING TO THE INVENTION A suppository mould is prepared according to the method of Example 1. A wax base is melted to a temperature just above its solidification point. The molten wax is then poured into the mould, allowed to cool and solidify. In this way a suppository of the same shape as that produced according to the method of Example 1 is formed. It also has the advantages discussed above in Example 1.

EXAMPLE 4: PREPARATION OF A WAX BASED SUPPOSITORY FOR THE DELIVERY OF HYDROCORTISONE A suppository mould is prepared according to the method of Example 1. A wax base is melted to a temperature just above its solidification point. Hydrocortisone and sodium lauryl-sulphate as surfactant are added to the molten wax with agitation to provide a homogenous mixture. The molten mixture is then poured into the mould, allowed to cool and solidify. A suppository of the same shape as that formed according to the method of Example I is formed. It also has the advantages discussed above in Example 1.

EXAMPLE 5: METHOD FOR THE PREPARATION OF A GELATIN BASED SUPPOSITORY ACCORDING TO THE INVENTION COMPRISING A SINGLE CONSTRICTION A suppository as illustrated in Figures 4 and 5 is prepared using a pre-formed suppository mould following the method described in Example 1.

The suppository formed by this method has a proximal end (1), a central portion (2) having a single constriction (3) which is disposed approximately in the centre of the suppository and a distal end (4). The proximal end (1) has tapered sides which form an apex, this increases the ease of insertion of the suppository into the rectum. The distal end (4) also has tapered sides which form an apex, providing a surface on which the anal sphincters may act to propel the suppository further into the rectum, increasing the ease of insertion of the suppository into the rectum. The shape of the distal end (4) also improves the body's ability to retain the suppository in use because the anal sphincters continue to act on it pushing the suppository further into the rectum and preventing it from being expelled. Furthermore because the two ends of the suppository are identical it can be inserted via either end without affecting it's effectiveness.

The single constriction (3) provides further surfaces on which the anal sphincters may act to propel the suppository further into the rectum. They further increase the ease of insertion of the suppository into the rectum and further improve the body's ability to retain the suppository after insertion.

The insertion of the suppository into the rectum is improved to the extent that many users will not need to insert a finger into the anal canal when using it.

Claims (22)

1. A suppository for insertion into an orifice of a human or animal body comprising an elongated body having a proximal end adapted to be inserted into the orifice, a distal end adapted to lie within the orifice after insertion and a central portion between the ends, the surface of the central portion being provided with one or more spiral or annular projections and/or depressions.

2. A suppository as claimed in claim 1, wherein the suppository comprises a noncompressed body.

3. A suppository as claimed in claim 1, wherein the suppository comprises a moulded body.

4. A suppository as claimed in any one of claims 1 to 3, wherein the suppository is solid.

5. A suppository as claimed in any one of claims 1 to 4, wherein the projections are ridges or pimples.

6. A suppository as claimed in claim 5, wherein the central portion comprises tapered ridge portions.

7. A suppository as claimed in claim 6, wherein the ridge portions taper from the first end portion of the suppository towards the second end portion.

8. A suppository as claimed in any one of claims 5 to 7, wherein the suppository comprises two tapered ridge portions.

9. A suppository as claimed in Claim 8, wherein the ridge portions are spaced approximately equidistant from the ends of the length of the suppository.

10. A suppository as claimed in claim 8 or claim 9 wherein the second end portion at its widest point is of substantially identical dimensions to the tapered ridge portions.

11. A suppository as claimed in any one of claims 1 to 10 wherein the suppository is a rectal suppository.

12. A suppository as claimed in any one of claims 1 to 11 suitable for the local treatment of haemorrhoids.

13. A suppository substantially as herein described with Reference to Figure 1.

14. A method for the preparation of a suppository according to any one of Claims 1 to 13 comprising: i) pouring a base material into a mould shaped to provide a suppository having a) a proximal end adapted to be inserted in the orifice, b) a central portion having one or more spiral or annular projections and/or depressions, and c) a distal end portion adapted to lie within the orifice after insertion.

and ii) allowing the base material to set within the mould.

15. A method for the preparation of a suppository according to any one of Claims 1 to 13 comprising: i) melting a wax base to a temperature above its solidification point, and ii) pouring the molten wax into a mould shaped to provide a suppository having a) a proximal end adapted to be inserted in the orifice, b) a central portion having one or more spiral or annular projections and/or depressions, and c) a distal end portion adapted to lie within the orifice after insertion, and iii) allowing the filled mould to cool and solidify.

16. A method for the preparation of a suppository according to any one of Claims 1 to 13 comprising: i) preparing a mould shaped to provide a suppository having a) a proximal end adapted to be inserted in the orifice, b) a central portion having one or more spiral or annular projections and/or depressions, and c) a distal end adapted to lie within the orifice after insertion.

ii) pouring a base material into the mould and iii) allowing the base material to set within the mould, or ii) melting a wax base to a temperature above its solidification point, iii) pouring the molten wax into the mould, and iv) allowing the filled mould to cool and solidify.

17. A method for the preparation of a suppository as claimed in any one of Claims 14 to 16 wherein the mould is formed from thermosetting material and the method further comprises sealing the mould around the suppository formed to provide a packaged suppository.

18. A method for the preparation of a suppository comprising an active agent according to the method of any one of Claims 14 to 16 wherein the therapeutic agent is added to the base material prior to pouring it into the mould or is added to the molten wax with agitation to provide a homogenous mixture which is poured into the mould.

19. A mould for the use in the preparation of a suppository as claimed in any one of claims 1 to 13.

20. A method for the administration of a material to a human or animal body comprising the use of a suppository according to any one of claims 1 to 13.

21. A method as claimed in claim 20 wherein the material is pharmaceutical or a prophylactic material.

22. A method for the alleviation of a condition of a human or animal body comprising the insertion of a suppository according to any one of claims 1 to 13 into an orifice of a human or animal body.