CA1238274A

CA1238274A - Dry, water-foamable pharmaceutical compositions

Info

Publication number: CA1238274A
Application number: CA000475180A
Authority: CA
Inventors: Leonard Chavkin
Original assignee: Health Products Development Inc
Current assignee: Health Products Development Inc
Priority date: 1984-02-29
Filing date: 1985-02-26
Publication date: 1988-06-21
Also published as: US4613497A; JPS60222427A; EP0153836A2; EP0153836A3

Abstract

ABSTRACT OF THE DISCLOSURE

A substantially anhydrous foamable composition capable of forming a substantially stable foam on contact with water is formed from a mixture of water soluble polysaccharide gum, an effervescent base and a biocompatible gelling salt. These compositions upon contact with water form extremely stable foams which are capable of acting as carriers for pharma-ceutically active compositions.

Description

I I

BACKGROUND OF TOE INVENTION

The use of foams for pharmaceutical purposes is well known particularly in the field of contraception as vaginal foams and in the treatment of hyperacidity as antacid foams. The effectiveness of both types of foams has been hindered by the short life such foams in the aqueous environment in which both find themselves.
While foaming action is quite simple to initiate the very presence of the environmental aqueous fluids which initiate the foaming serve to rapidly dilute the foam to a point where it no longer exists in this form. A
composition capable of foaming rapidly on the one hand outproducing a foam with a substantial foam life is a long felt need. Such foaming compositions provided that they are made of biochemically compatible materials can be utilized as carriers or sustained release I
devices for numerous pharmaceutically active compositions.

SUMMARY OF TOE INVENTION

It has been found that substantially an hydrous i compositions capable of forming a substantially stable foam on contact with water may be formulated from Mecca lures comprising a water soluble polysaccharide~ gum a water soluble biocompatible calcium or potassium golfing salt and an effervescent base comprising an alkali metal carbonate or bicarbonate and a water soluble biocompatible acid or acid salt. Such compost-lions may be compounded with a pred2termined~pharma-ceutically active material and provided in any of the usual dosage forms such as tablets, capsules powders granules, or suppositories. The Compositions may then :, .
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be administered in a conventional manner suitable for their in-tended purpose. Suitable foci for administration are ox for gastric ally active compositions and intravaginally for vaginal contraceptives, buffers and the like.

DESCRIPTION OF THE PREFERRER _ M~ODIM~N~S

The substantially an hydrous formable compositions of the present invention comprise 20 to 75 parts by weight, suitably about 30 to 50 parts by weight of a water soluble polysaccharide gum. Among the suitable I, gums may be mentioned the water soluble allegiant salts such as sodium or potassium allegiant and kappa carry genuine as well as iota carrageenan. There is also provided a golfing agent to provide a rubbery polymer ; 15; salt, said salt comprising between about 10 to about 50, suitably between about 20 to about 30 parts by weight of teetotal composition. The golfing salt can be any water soluble biocompatible calcium salt such as the gluconate, lactate, chloride or less soluble salts 20~ if required for slower golfing such as carbonate or phosphate Where kappa carrageenan is utilized as the polysaccharide~gum, the corresponding potassium salts May be employed. It is preferred to utilize an amount Jo of water soluble salt corresponding to between 10 and 25~ 100% by weight of the gum in the composition ;

The foaming effsot is achieved Beth presence Of an effervescent base the term base here not being utilize din its meaning sinuses opposite or complex méntary tweezed). The base comprises a gas generating component most suitably carbonate or bicarbonate preferably sodium or potassium bicarbonate and an acid component selected from any solid water soluble boo-I

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compatible acid such as the fruit acids suitablytartaric, mafia, fumaric, adipic or citric acids, or acid salts such as sodium biphosphate. In the preferred embodiment of the invention, substantially equal parts by weight of the gas generating component and the acid are utilized.

A large variety of pharmaceutically active compositions can be incorporated into the compositions and the compositions formulated into conventional modes of administration.

For purposes of the following discussion, the standard dosage unit will be considered as comprising one gram of Guam grams of alkali metal bicarbonate, 0.5 grams of biocompatible acid, and 0.5 grams of jollying salt. Such a dosage unit is merely considered to be illustrative and no way to be considered as limiting the scope of the present invention.
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Vaginal contraceptive composition may be pro-pared comprising the basic formable composition and a spermicide. Any known vaginal active spermicide may ; be employed in particular, there may be mentioned ` nonoxynol-9, octoxonol or mefengol These are come pounded in dosages of between 50 to 200, suitably between 75 and 100 my. per dosage unit.

25~ A vaginal buffering agent may be provided by in-;
creasing~the~amount of the biocompatible acid by between 250 and 1,0~00, most suitably between 300 and :
I` 500 mg./dosage unit of acid.
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Another use for the compositions may be found as :
gastric antacid agents. In this composition, there are additionally utilized carbonates such as calcium ::
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07: magnesium carbonate or the hydroxides of aluminum, magnesium or bismuth. These are merely considered to be the common and exemplary materials but other boo-compatible bases could also be employed.

The stable nature of the foam produced by the foaming compositions of the present invention make the foams particularly suitable as gastrointestinal depots operating as sustained release agents for a variety of pharmacologically active agents which are trade-lo tonally administrable by a gastric route As I exemplifying but not limiting this aspect of the in-mention may be mentioned sympathomimetic amine such as phenylpropanolamine and solutes ephedrine and salts, isoproterenol and salts, phenylephrine and salts or pseudoephe~drinè and salts, antihistimes such as chlorphaniramine, diphenhydramine, docylamine, phenol-toloxamine, pyrilamine, tripelenarnine~ pheniramin~e~ b brompheniramine, dexbrompheniramine~ dexchlorpheniramine, ; promethaz1ne, meclizine or cyclizine, antltuszives;~
;20 swish as ~dextromethorphan, benzonatate, noscapine, Corey ; betapentane~citrate, cararniphen ethanes disulfonate~
or chlorphedianol, analgesics swishes aspirin, z~cetzminophen,~salicylzmide, sodium sustained Mathewson ibuprofen or phenylbutazo`ne~ and Mazola ;25~ relaxants such as car1soprodol, methoczrbamol;or~
meprobamzte.

It will be understood by those skilled in the art that pharmaceutically inert excipients~ dilueDts~and~
the~like~c~an be included in the compositions as desired The special advantage of~the~aompozit10ns~of the present invention Lucy in the desirable combination of ': :, ~3~27~L

immediate action and long life compared to conventional foams. For example, currently available vaginal contraceptives tablets and suppositories require a 10 to 15 minute waiting period for the foam to develop as opposed to the 2 to 5 minute time required by the present compositions, and the present compositions maintain their structure for up to 6 hours as opposed to one hour for conventional products. These two properties are extremely important in considering the esthetics of use as vaginal contraceptives permitting ; on the one hand substantially instantaneous intercourse where this is desired and on the other hand, an unobvious "preplanning" if that approach is desired.

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Specific FORMULATIONS

EXAMPLE I
Vaginal Contraceptive Composition MaterialMg~dosage Unit Sodium Allegiant 500 Jo Sodium Bicarbonate 500 : Citric Acadia Calcium Gluconate 200 Nonoxynol 9100 :
Lactose 500 - : TOTAL 2,300 Jo :
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:~. Example II
Vaginal Buffering Agent Ed Suppository MaterialMg/dosaqe Unit : Sodium Allegiant 850 Sodium Bicarbonate 500 :
Citric Acid 1~000 ;
; : : Calcium Gluconate 200 :
I; 20 Polyethylene Glycol 1540 Lowe Polyethylene Glycol 4000 :250 : TOTAL 3~300 :~.:: : : . :

: The mutters of Examples I and Icon be grant-: : fated tub compressed in a conventional tabulating machine.

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EXAMPLE III
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Gastric Antacid Material Material Mg/dosage Unit Iota carrageenan 200 Sodium Bicarbonate 150 Tartaric Acid 150 Calcium Carbonate loo Aluminum hydroxide 200 Magnesium hydroxide 200 TOTAL Lowe This mixture can be granulated to be compressed in a conventional tabulating machine or filled into a powder dispenser , XXrmPLX IV
_ Formula Pseudoephedrine 120 m (a 12 hour Hydrochloride g dose) Kappa carrageenan 250 my.
'I Sodium Bicarbonate 125 my.
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Citric Acid 125 my.
Potassium Gluconate 250 my.

TOTAL B70 my. or 435 my.
per tablet :

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Process Mix all ingredients, granulate with 75% isopropanol, Dry, lubricate with I calcium Stewart and compress into tablets, In accordance with the above procedure but in place of pseudoephedrine hydrochloride, there is utilized chlorpheniramine Malta 12 my. or dexter-methorphan hydrobromide 120mg,, a similar product (2 tablets, 12 hr. dose) is obtained.
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o EXAMPLE V
Gastric Antacid Tablet Jo Formula Per Dose (Film Coated Tablet) Potassium Bicarbonate 500 my. I me, K) , ~15 Citric Acid 150 my, Sodium Allegiant 250 my.
Dicalcium Phosphate loo dehydrate Process Granulate and compress as in Example I, Film 20~ coat tablets for easy swilling :: : :

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Analgesic Composition Formula Per Dose (2 tablets) Acetaminophen, 1,300 my (an 8 hr.
powder dose) S A composition is prepared in accordance with Example IV but substituting acetaminophen for pseudo-ephidrine.
Two tablets provide sustained blood levels of acetaminophen over an eight hour period equal to two lo divided doses of 650 my. each at four hour intervals EXAMPLE VII
Muscle Relaxant Composition Formula Per Dose (2 tablets) -Carisoprodol, powder 700 my. (a 12 hr. dose) A composition is prepared in accordance with Example IV but substituting acetaminophen for pseudo ephidrine Two tablets provide sustained blood levels of carisoprodol over an eight hour period equal to two divided doses of 350 my. each at four hour intervals.

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EXAMPLE VIII
Contraceptive Gel for delivery by means of MaterialMq. Per Dosage Unit Nonoxynol-9 100.0 Sodium Allegiant 800.0 Sodium Bicarbonate 500.0 Citric Acid 500,0 Polyethylene Glycol 1500 1000,0 Calcium Gluconate 200.0 :
TOTAL 3100.0 my.
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Claims

CLAIMS:

1. A substantially anhydrous foamable composition capable of forming a substantially stable foam on contact with water comprising a) 20-75 parts by weight of a water soluble polysaccharide gum, b) 10 to 50 parts by weight of an effervescent base comprising an alkali metal carbonate or bicarbonate and a water soluable biocompatible acid or acid salt and c) 10% to 100% by weight relative to the weight of gum used, of a biocompatible calcium or potassium gelling salt.

2. A composition of Claim 1 wherein;
a) the gum is selected from the group consisting of sodium or potassium alginate, sodium kappa carra-geenan or sodium iota carrageenan, b) the acid component of the effervescent base is a fruit acid or a biocompatible acid salt and c) the gelling salt is selected from the group consisting of calcium gluconate, lactate, citrate, formate, chloride, carbonate, dicalcium phosphate dihydrate provided that where the gum is kappa carra-geenan then the salt is the corresponding potassium salt. :

3. A sustained release gastric depot composition for the administration of gastrically administrable pharmaceutically active compositions comprising a composition of Claim 1 and an effective amount of said pharmaceutically active composition.

4. A sustained release gastric depot composition for the administration of gastrically administrable pharmaceutically active compositions comprising a composition of Claim 2 and an effective amount of said pharmaceutically active composition.

5. A sustained release vaginal depot composition for the administration of vaginally administrable pharmaceutically active compositions comprising a composition of Claim 1 and an effective amount of said pharmaceutically active composition.

6. A sustained release vaginal depot composition for the administration of vaginally administrable pharmaceutically active compositions comprising a compo-sition of Claim 2 and an effective amount of said pharmaceutically active composition.

7. A composition according to Claim 3 wherein the amount of pharmaceutically active composition is between 1 and 50% by weight of the weight of the foamable composition

8. A composition according to Claim 4 wherein the amount of pharmaceutically active composition is between 1 and 50% by weight of the weight of the foamable composition.

9. A composition according to Claim 5 wherein the amount of pharmaceutically active composition is between 1 and 50% by weight of the weight of the foamable composition.

10. A composition according to Claim 6 wherein the amount of pharmaceutically active composition is between land 50% by weight of the weight of the foamable composition.

11. A contraceptive composition of Claim 9 introducable into the female vagina in dry form com-prising said foamable composition and between 1 and 50%
by weight of said composition of a spermicidally active composition.

12. A contraceptive composition of Claim 10 introducable into the female vagina in dry form com-prising said foamable composition and between 1 and 50%
by weight of said composition of a spermicidally active composition.

13. A composition of Claim 12 wherein the spermicide is nonoxynol, octoxonol, or mefengol.

14. A composition of Claim 13 wherein the spermicidal composition comprises between 2 and 8% by weight of the foamable composition.

15. A gastric antiacid composition of Claim 3 comprising said foamable composition and a gastric antiacid material.

16. A composition in accordance with Claim 15 wherein the antiacid material comprises at least one member selected from the group consisting of basic salts of calcium, magnesium, aluminum, or bismuth or the hydroxides thereof.

17. A composition of Claim 16 wherein the anti-acid material comprises between 10 and 40 wt. percent of the foamable composition.

18. A vaginal buffering agent in accordance with Claim 5 which comprises said foamable composition and an additional amount of said acid component.

19. A composition in accordance with Claim 18 wherein the amount of acid is between 10 and 40% by weight of the foamable composition.

20. A composition in accordance with Claim 3 wherein the pharmaceutically active ingredient is selected from the group consisting of sympathomimetic amines, antihistamines, antitussives, analgesics and muscle relaxants.

21. A composition of Claim 20 wherein the sympathomimetic amines are selected from the group consisting of phenylpropanolamine, ephedrine, and pseudoephedrine, the antihistamines are chlorpheniramine, the antitussives are dextromethorphan, and the anal-gesics are acetaminophen.