IE50986B1 - Compositions comprising phenolphthalein - Google Patents

Description

Inflammatory viral infections may be caused in humans and other mammals and animals by a wide variety of viruses. A common virus which produces conditions which have proved persistently hard to treat is the Herpes Simplex virus (which exists in two Types,. In humans, the Type I virus normally produces above-waist infections, while the Type II virus produces lesions below the waist, in the genital region. Common manifestations of viral infection, including Herpes Simplex I infections, are labialis (cold sores, fever blisters), pharyngitis, keratitis, skin infections (herpetic whitlow), encephalitis, and chronic ulcerative stomatitis. Herpes Simplex Type II may cause progenitalis oropharyngeal infections, meningitis and encephalitis. Other manifestations of inflammatory viral infections are canker sores, sun blisters and other such, skin lesions and ulcerous conditions. In mammals such as cows, bulls and sheep, both Types I and II infect eyes, ears, mouth and upper respiratory systems. Birds, such as parrots, are virally infected in their digestive tracts, among other regions, by what is known as New Castle disease.

Inflammatory viral infections have proven very difficult to treat, and in many instances are allowed to run their course with symptomatic treatment such as ointments or local anaesthetics. Treatment for Herpes Simplex infections includes dusting with bismuth formic iodide, application of camphor spirit, epinephrine, idoxuridine, adenine arabinoside or large doses Of steroids, and X-ray or grenz ray therapy.

Inflammatory skin conditions (dermatitis) Which occur frequently include photodermatitis and actinic dermatitis such as sunburn and actinic keratosis, eczema pruritus, acute and chronic lesions, burning, swelling and - 3 blistering. These conditions are difficult to treat with moisturising creams, lotions and other topical agents.

Acne is a disease of the pilosebaceous unit which includes the hair follicle and its sebaceous gland.

These units are most numerous on the face but also are found in abundance on the back, chest and upper arms; see Kaminester, Journal of the American Medical Association 239 (20) 2171-72. Normally, the sebaceous glands secrete an oily material called sebum which rises to the top of the hair follicle and then flows out onto the skin surface. Bacteria, chiefly Corynebacterium acnes, live in the hair follicles and break down complex fats into triglycerides and free fatty acids. Acne occurs when the canals through which the oily sebum flows become plugged up. The plugged hair follicle, or comedo, often ruptures into the lower skin areas and dumps free fatty acids, horn, fat, hair and bacterial products into the dermis, creating a toxic foreign body response which can cause scarring.

It has been recommended to treat acne with oral antibiotics which effectively decrease the bacterial count of C. acnes. Such antibiotics include tetracycline and erythromycin, which selectively concentrate around the hair follicles, thus reducing the C. acnes count and subsequent inflammation. These antibiotics may also be applied topically. Topical tetrinoin and benzoyl peroxide preparations have had beneficial effects in the treatment of acne. Kaminester, supra, reports that topical application of antibiotics is inferior to oral administration, and should not be used in severe cases of inflammatory acne.

Arthritis is the inflammation of a joint, usually accompanied by pain. It can result from a number of conditions, including infection, trauma and degenerative joint diseases. Rheumatism is an acute or chronic S Ο 9 8 6 - 4 condition characterised by soreness and stiffness of muscles, and pain in joints and associated structures. Rheumatoid arthritis is a systemic disease characterised by inflammatory changes in joints and related structure. It tends to be chronic. There is no specific cure, and physical therapy and orthopaedic measures are often used in treatment.

Phenolphthalein has long been known as one of a group of primary diphenylmethane carthartics. The cathartic effect of phenolphthalein was reportedly discovered in 1902 and, since that time, it has been widely employed in laxative formulas. It is also reported that phenolphthalein is relatively non-toxic; see Goodman 6 Gillman, Pharmacological Basis of Therapeutics, 4th Ed. (1977), 1021 and 1022. Phenolphthalein is also used as an indicator in titrations of mineral and organic acids and most alkalies.

It is well known that phenolphthalein is highly insoluble in water. When phenolphthalein is ingested into the human body, less than 15% of the active drug in solution is absorbed into the blood stream. The rest of the drug is excreted in the faeces.

A dry composition according to the present invention comprises a water-solubilised mixture of phenolphthalein and an alkali metal bicarbonate. An agueous solution according to the invention comprises a water-solubilised mixture of phenolphthalein and an alkali metal bicarbonate. Preferably, there are about 4 parts by weight phenolphthalein per part by weight bicarbonate.

The bicarbonate is preferably sodium bicarbonate.

A dry mixture according to the invention can be prepared by adding water to a mixture of phenolphthalein and the bicarbonate, to form a paste, and heating the paste to less than the boiling point of water for a time sufficient to evaporate substantially all the water. 50386 - 5 This method gives a substantially anhydrous mixture which can be ground into a powder, and the powder can be dissolved in hot or cold water.

In the method of the invention, it is preferred that about 1.75 g of the mixture are used per g water. The method preferably includes the addition of dimethyl sulfoxide (DMSO). The method may also be adapted to include the addition of a topical carrier or a carrier suitable for ingestion.

It is an important advantage of the invention that phenolphthalein can be rendered, for use, almost completely water-soluble. A solution can be applied to an afflicted human or other mammal or animal, hypodermically, intramuscularly, intravenously, subcutaneously, topically or by ingestion.

A pharmaceutical composition according to the invention, adapted for ingestion, comprises a dry mixture or solution of the invention, and an ingestible carrier. Such compositions can be used for the treatment of inflammatory viral infections, acne, rheumatism and arthritis, e.g. rheumatoid arthritis. They may be provided in tablet, capsule or similar form.

A pharmaceutical composition according to the invention, adapted for topical application, comprises a dry mixture or solution of the invention and a topical carrier. Preferably, the topical composition comprises from 5 to 9 g phenolphthalein per g of the topical carrier. The dry mixture or solution may be dispersed in the topical carrier. The topical carrier may be selected from petrolatum, mineral oils, anhydrous lanolin, polyethylene glycol, methyl salicylate, triethanolamine salicylate, polyvinyl alcohol, benzalkonium chloride, phenyl mercuric nitrate, sodium chloride, boric acid and disodium edetate, and combinations thereof.

A topical composition of the invention may be used - 6 to relieve or cure Herpes Labialis, cold sores, sun blisters, canker sores, photodermatitis, actinic dermatitis, actinic keratosis and dermatitis manifested as pruritus, acute and chronic lesions, burning, swelling and blistering. In a topical preparation including an antibiotic, for the treatment of acne, the carrier will not comprise comedogenic agents.

For external application, a suitable carrier can aid in application to, or absorption into, the target or affected area. One group of carriers for external application comprises oil-based carriers such as DMSO, petrolatum, mineral oil and anhydrous lanolin. Another carrier useful in external application is the mixture of 10% methyl salicylate and lanolin, with 20% phenolphtha15 lein. Triethanolamine salicylate can be substituted for the methyl salicylate. Polyethylene glycol, as a carrier, is also effective in external applications.

DMSO may be mixed with an agueous solution of the invention. The resultant solution may then be combined with any suitable base cream, ointment or other carrier such as lanolin or petrolatum.

While it has been found that phenolphthalein is efficacious in treating Herpes Simplex infections, acne and cold and influenza symptoms, it roust usually be accepted that only 15% of the phenolphthalein administered is absorbed into circulation. The use of a water-soluble mixture, or aqueous solution, according to the invention allows this amount to be increased. This is consequent on the fact that the human body and mammal30 ian circulatory systems and body fluids are water-based. The following Examples illustrate the inventionEXAMPLE 1 parts by weight phenolphthalein, a N.F. purified grade of 3,3-bis(p-hydroxyphenyl)phthalide, and 1 part by weight sodium bicarbonate (NaHCOj), both in powdered - 7 form, were mixed thoroughly and then moistened lightly with distilled water to form a mixture with a paste consistency. Within less than 5 minutes, this paste was then heated to about 80 C for about 30 minutes. At the end of this period substantially all the moisture had evaporated. The resulting mixture was then crushed to a powder consistency.

The powder can be made into tablets, or paste in which gelatin capsules, for application by oral ingestion.

EXAMPLE 2 200 mg of the powder prepared by the procedure of Example 1 were completely dissolved in 113 g (4 oz) hot water at 49 to 77 C (120 to 170°F) to form a solution.

The resulting solution was ready for application topically or by injection or direct ingestion.

EXAMPLE 3 The dry powder prepared by the procedure of Example 1 was dissolved in cold water, with stirring. After about 5 minutes, a stable solution was formed. The solution was ready for application topically or by injection or ingestion.

EXAMPLE 4 The procedure of Example 1 was followed, except that the paste was heated to about 93 C. The time for the water to evaporate was reduced to less than 30 minutes. EXAMPLE 5 The procedure of Example 1 was modified by varying the phenolphthalein:bicarbonate ratio to from 1:2 to 10:1 w/w. Water-soluble preparations were obtained.

COMPARATIVE EXAMPLES By comparison with Example 1,·200 mg of the mixture of powders was instead immediately mixed with 113 g (4 oz) hot water at 49 to 77 C (between 120 and 170’F), with stirring. Not all the phenolphthalein dissolved in 986 - 8 the alkaline solution of sodium bicarbonate. Instead, a suspension of phenolphthalein was formed. Within approximately 3 minutes, about 50% of the phenolphthalein settled out of solution.

For further comparison, 50 mg sodium bicarbonate were dissolved in hot water, with stirring. 200 mg phenolphthalein were added to this solution, and stirring took place for approximately 15 minutes. The phenolphthalein settled out of the solution very rapidly after stirring ceased. Approximately 50% of the phenolphthalein settled out in less than about 5 minutes.

Again for comparison, phenolphthalein powder was moistened with water and thereafter heated and dehydrated. The product was a dry phenolphthalein powder. Sodium bicarbonate powder was moistened to paste consistency with water and heated to dryness. The sodium bicarbonate thus prepared was dissolved in hot water.

The previously-treated phenolphthalein was added to this solution. The phenolphthalein required approximately 10 to 15 minutes of stirring to form a suspension. Within 5 minutes after stirring ceased, the phenolphthalein started to settle out.

Claims (10)

1. A dry, water-solubilised mixture of phenolphthalein and an alkali metal bicarbonate.

2. An aqueous solution comprising a water-solubilised mixture of phenolphthalein and an alkali metal bicarbonate.

3. A mixture or solution according to claim 1 or claim 2, which comprises about 4 parts by weight phenolphthalein per part by weight bicarbonate.

4. A mixture or solution according to any preceding claim, in which the bicarbonate is sodium bicarbonate.

5. A method for preparing a dry mixture according to claim 1, which comprises adding water to a mixture of phenolphthalein and an alkali metal bicarbonate, to form a paste, and heating the paste to less than the boiling point of water for a time sufficient to evaporate substantially all the water.

6. A method according to claim 5, which includes the addition of dimethyl sulfoxide.

7. A method according to claim 5 or claim 6, which comprises using about 1.75 g of the mixture per g water.

8. A pharmaceutical composition, adapted for ingestion, which comprises a mixture or solution according to any of claims 1 to 4, and an ingestible carrier.

9. A pharmaceutical composition, adapted for topical application, which comprises a mixture or solution according to any of claims 1 to 4, and a topical carrier. 10. A composition according to claim 9, which comprises from 5 to 9 g phenolphthalein per gram of the carrier. 11. A composition according to claim 9 or claim 10, in which the carrier is selected from petrolatum, mineral oil, anhydrous lanolin, polyethylene glycol, methyl salicylate, triethanolamine salicylate, polyvinyl alcohol, benzalkonium chloride, phenyl mercuric nitrate, sodium chloride, boric acid and disodium edetate. 12. A composition according to any of claims 9 to 11, in which the mixture or solution is dispersed in the carrier. - 10 50886 13. a dry water-solubilised mixture according to claim 1, substantially as hereinbefore described and exemplified. 14. An aqueous solution according to claim 2, substantially as hereinbefore described and exemplified. 5 15. A method according to claim 5 for preparing a dry mixture, substantially as hereinbefore described and exemplified. 16. A dry mixture whenever prepared by a method claimed in a preceding claim.

10. 17. A pharmaceutical composition according to claim 8, substantially as hereinbefore described and exemplified.