Foam-forming pharmaceutical composition

Details Foam-forming pharmaceutical composition Foam-forming pharmaceutical composition

1998-09-24

2001-07-10

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S430000, C424S431000

Reexamination Certificate

active

06258374

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides a pharmaceutical composition for rectal or vaginal administration and its use in therapy.
BACKGROUND OF THE INVENTION
Various means of administering drugs to the intestine are known. For example oral controlled release compositions are used to reach the upper part whereas enemas are used to reach the lower part. Enemas are usually used in the form of a foam to overcome the problem of leakage from the rectum following administration which makes it necessary for patients to lie down during administration. Foams, as well as pessaries, tampons and creams are used to administer drugs to the vagina.
Conventional foams for rectal or vaginal administration are filled in pressurised containers with a pharmaceutically active ingredient dissolved or suspended in a liquid vehicle, at least one propellant gas and a surfactant with foaming properties. Examples based on mesalazine, peppermint, sucralfate or budesonide as the active ingredient dispersed in a liquid vehicle containing a foaming surfactant and administered for topical action in the colon using a pressurised atomiser with a propellant gas are described in EP-A-468 555. Rectal foams formed by a propellant gas on expulsion from a pressurised container and containing other active ingredients such as flunisolide and its derivatives (see WO 94/12187), 5-aminosalicylic acid (EP 395 329), and 4-aminosalicylic acid (DE 4316724) have also been described.
Chlorofluorocarbons are generally used as the propellant gas but these are undesirable for environmental reasons. Also the use of pressurised containers to administer pharmaceutically active substances suffers from a number of problems. For example, it is difficult to administer an accurate dose of the pharmaceutical composition of the drug; the containers are difficult to store over long periods of time because of leakage of gas which results in reduced administration capacity. Furthermore the disposal of used containers can be dangerous because of the risk of explosions on incineration. Accordingly alternative formulations need to be found.
DESCRIPTION OF THE INVENTION
According to the invention there is provided a pharmaceutical composition for rectal or vaginal administration which comprises at least two parts wherein the composition comprises
(i) two or more physiologically acceptable substances each in separate parts of the composition which are such that on admixture they react to produce a physiologically acceptable gas;
(ii) in at least one part of the composition a polymer stabiliser which is adapted to facilitate the formation of a water-soluble collapsible foam structure; and
(iii) in at least one part of the composition a pharmaceutically active substance.
During administration the individual parts of the composition are mixed which causes the two or more substances defined in (i) to react to produce a gas which contacts the polymer stabiliser (ii) forming a water-soluble collapsible foam which may then be applied to the rectum or vagina. The polymer stabiliser is preferably used in a swelled form, e.g. in the form of a hydrogel. The composition of the invention is preferably administered from a multi-part syringe. The advantage of such a device is that the foaming action is smooth and the time for the administration is controllable using the piston of the syringe resulting in less discomfort for the patient.
The two or more substances defined in (i) are preferably one or more acids, especially water-soluble acids and one or more effervescent compounds. Each is generally used as an aqueous solution in a concentration of from 0.1 to 10% by weight of the compositions.
The acid is preferably hydrochloric acid or a water-soluble mono- or polycarboxylic acid. Examples of suitable water-soluble mono- or polycarboxylic acids include citric, lactic, tartaric, succinic, glycollic, malonic, oxalic, malic, flumaric, maleic, or acetic acid. Most preferred is citric acid, preferably in a concentration of from 1 to 3% by weight of the composition.
The effervescent compound is preferably a pharmaceutically acceptable alkali metal carbonate or bicarbonate e.g. sodium monohydrogen carbonate, potassium monohydrogen carbonate, sodium carbonate or potassium carbonate. Most preferred is sodium monohydrogen carbonate, preferably in a concentration of from 3.5 to 5.5% by weight of the composition. The exact concentration of each substance to be used depends on the volume of foam required and the desired pH and osmolarity of the foam to be formed. Generally where the two substances (i) are an acid and an effervescent compound, they should be used in a ratio of from 1:0.5 to 1:25, preferably from 1:1 to 1:4, by weight of the acid to the effervescent compound.
The polymer stabiliser (ii) is preferably a hydrogel thickener. The polymer stabiliser used in the invention preferably displays pseudoplastic flow characteristics when in solution. More preferably the polymer stabiliser used in the invention is a water soluble hydrogel thickening polymer, e.g. a natural polysaccharide, semi-synthetic polymer or a synthetic polymer, or a mixture thereof Examples of natural polysaccharides are agar, alginates, carrageenan, guar, arabic, tragacanth, pectins, dextran, gellan and xanthan gums. Suitable semi-synthetic polymers are polysaccharide derivatives, e.g. cellulose esters and modified starches. Examples of synthetic polymers are polyvinyl alcohol, polyvinylpyrrolidone, polyacrylates, polyvinylacetate, and poloxamer. Preferably the viscosity of a solution thickened with the polymer stabiliser is remains substantially the same in a wide pH range and is relatively independent of ionic strength. More preferably the polymer stabiliser is xanthan gum or hydroxyethyl cellulose. Most preferably the polymer stabiliser is xanthan gum.
The advantage of xanthan gum is that compositions containing it have a low viscosity at high shear rates, therefore they are easy to pump, spray and spread. They exhibit a high viscosity at low shear rates. This results in a good stabilisation of suspended drugs.
The polymer stabiliser is preferably used in such concentrations that solutions or dispersions containing it in swelled form have a viscosity as measured by Bohlin® rotational viscosimeter CSR-10a within the ranges shown in Table 1 at the given shear rates. The concentration of a given polymer stabiliser required to meet the viscosity requirements may easily be determined empirically by a person of skill in the art.
TABLE 1
Viscosity Range
Preferred Viscosity Range
Shear Rate (s
−1
)
(mPas)
(mPas)
0.1
10
1
-10
10
10
3
-10
7
1
10
1
-10
9
10
2
-10
5
10
10
1
-10
8
10
2
-10
4
100
10
1
-10
5
10
2
-10
3
In general the concentration of the polymer stabiliser should be from 0.1 to 5% by weight of the composition where it is xanthan gum or hydroxyethyl cellulose. Preferably the concentration of xanthan gum used is from 0.5 to 2% by weight of the composition and the concentration of hydroxyethyl cellulose where it is hydroxyethyl cellulose 4000 is from 2 to 3% by weight of the composition. When the polymer stabiliser is PVP 90, it is preferably used in a concentration of from 5 to 30% by weight of the composition, preferably 10 to 25% by weight.
The pharmaceutically active substance to be used in the present invention depends on the disease to be treated by the composition or intended effect of the composition. It is preferably one or more of an anti-inflammatory drug, analgesic, local anaesthetic, anti-infection drugs, contraceptive and/or an anti-anginal agent. Suitable anti-inflammatoy drugs include steroids or non steroidal anti-inflammatory drugs (NSAIDs). Preferred analgesics and local anaesthetics are lidocaine, morphine or codeine. Preferred steroids are budesonide, suitable esters of beclomethasone, rofleponide or suitable derivatives (e.g. esters) thereof, hydrocortisone, betamethasone, prednisolone, dexamethasone, fluocinolone, amcinonide, bufexamac or flunisolide. Particularly preferred is budesonide. Preferred NSAIDs are 4-aminosalicylic acid, 5-aminosalicylic acid

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