Title:  Method of treating HIV infection with transdermal gel containing mammalian liver extract

United States Patent:  6,350,472

Assignee:  Steinbach, Pylant, and Hermann, L.L.C. (Sealy, TX)

Filed:  December 14, 1998

A method for treating human immuno-deficiency virus infection (HIV-1), comprising administering a therapeutically effective amount of a mammalian liver extract characterized by being heat stable, insoluble in acetone, and soluble in water. A transdermal colloidal dispersion delivery system for use in the treatment of HIV-1 infection further comprises an emulsion of resolubilized, concentrated mammalian liver extract.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The portion of mammalian liver extract that has been discovered to be effective in treating HIV-1 infection is the fraction which is heat stable, insoluble in acetone, and soluble in water. As disclosed in U.S. Pat. Nos. 5,284,664, 5,316,775, and 5,334,395, it is believed that these polysaccharides are present in KUTAPRESSIN in the form of proteoglycans or glycoproteins.

A transdermal delivery system has been discovered to be a particularly effective method of delivering a mammalian liver extract, such as KUTAPRESSIN, when further concentrated according to the present invention. Such a transdermal delivery system allows the concentrated liver extract to be absorbed into the blood in concentrations apparently adequate for the treatment of HIV-1 infection.

Preparation of a Transdermal Colloidal Dispersion Delivery System for Kutapressin

The transdermal colloidal dispersion employed in the present invention is one of the preferred methods for administering the liver extract.

A soy lecithin gel is prepared from 10 grams of soy lecithin, to which 11.7 ml of isopropyl palmitate and 0.2 g of sorbic acid are added. The gel is then allowed to meld for 24 hours. A 20% poly(oxypropylene)-poly(oxyethylene) copolymer gel, such as Pluronic 127 (BASF), is prepared by adding 0.2 g of potassium sorbate and 100 ml of distilled water to 20 g of Pluronic 127. This gel is also allowed to meld for 24 hours.

Dessicated liver extract is used to prepare the gel formulation. One way in which this may be accomplished is described below by dessicating 3 vials (60 ml) of commercially available KUTAPRESSIN. A Nalgene dessicating system is set up using calcium sulfate as the dessicating absorbant. Two evaporating dishes containing the KUTAPRESSIN are placed in the apparatus and a vacuum is applied via a pump for 7 minutes. The dessicating absorbant must be changed every 24 hours, and the vacuum pressure must be reapplied after each change of absorbant to restore the vacuum. After 72 hours, the liquid will be absorbed, leaving only active ingredient.

Six ml of preserved water and 4 drops of phenol are added to the KUTAPRESSIN, and it is allowed to solubilize. This is the resolubilized liver extract preparation. The liquid is placed in a 30 ml syringe attached to another 30 ml syringe by a Luer Lock adapter. Seven ml of soy lecithin gel is added to the solubilized KUTAPRESSIN in the syringe. The liquids are transferred between the two syringes until an emulsion forms. With the syringes still attached and the emulsified liquid in one syringe, 17 ml of 20% Pluronic 127 is added to the empty syringe. The Pluronic 127 is then transferred to the KUTAPRESSIN emulsion. This results in a colloidal dispersion. The colloidal dispersion is then transferred between the syringes about 20 times to further emulsify the mixture. This final colloidal dispersion volume is about 30 ml, and it contains KUTAPRESSIN at a concentration of about 50 mg/ml.

It is also anticipated that a transdermal delivery system comprised of lecithin and other penetration enhancers; vehicles other than lecithin which alter the molecular environment of the epidermis; an adhesive patch containing a drug reservoir, with or without a rate controlling membrane, covered by an occlusive backing; iontophoresis; and phonophoresis may be used to deliver the liver extracts of the present invention.

Administration of Liver Extract

An acetone-insoluble liver extract useful in the present invention preferably is administered percutaneously, for example, using a transdermal colloidal dispersion delivery system in the form of a patch applied to the skin, or by applying the colloidal dispersion directly to the skin. However, other forms of administration are contemplated.

The liver extract may be employed in the form of pharmaceutically acceptable salts of the components, such as alkali metal salts. The pharmaceutically acceptable amides, lower alkyl esters, protected derivatives, other derivatives and analogs of the components of the liver extract are also contemplated.

While a transdermal colloidal dispersion formulation is preferred, other pharmaceutical carriers, for example, a saline solution, could be employed. The liver extract preferably is administered percutaneously while contained in a colloidal dispersion. A preferred product is a colloidal dispersion comprised of any of a variety of transdermal delivery vehicles and penetration enhancers containing KUTAPRESSIN which has been concentrated to a level of about 50 mg/ml. Iontophoretic and phonophoretic methods of introducing KUTAPRESSIN transdermally are also contemplated.

Dosages may vary depending upon the condition of the patient. Generally, however, it has been found that the administration of 400 mg of KUTAPRESSIN per day will produce beneficial results in as little as about 4 weeks.

CLINICAL OBSERVATION EXAMPLE 1

A patient infected with HIV-1 received 400 mg of KUTAPRESSIN percutaneously daily. Administration of the percutaneous colloidal dispersion composition was begun after Quantitative HIV RNA PCR analysis was used to determine the number of HIV RNA copies per ml of the patient's blood. The initial level of HIV RNA was documented as 18,000 copies/ml.

After receiving 400 mg of KUTAPRESSIN daily for 4 weeks, quantitative HIV RNA PCR analysis revealed that the patient's HIV RNA level dropped to 6,400 copies/ml. The dosage of KUTAPRESSIN was then lowered to 200 mg per day percutaneously. The patient's blood was tested to determine the HIV RNA level after approximately 10 weeks of treatment at this dosing level. The level of HIV RNA present was documented as 14,400 copies/ml.

Although the invention has been described previously in connection with special and preferred embodiments, it will be understood that it is capable of modification without departing from the scope of the invention. The following claims are intended to cover all variations, uses, or adaptations of the invention which follow, in general, the principles thereof and including any departures from the present disclosure that are within known or customary practices in the field to which this invention pertains, or as are obvious to persons of ordinary skill in the field.

Claim 1 of 9 Claims

We claim:

1. A method of treating an HIV-1 infection in a mammal by administering percutaneously, through a topical application to the skin, a therapeutically effective amount of a porcine liver extract in a colloidal dispersion through a composition comprised of:

a transdermal delivery system comprising a colloidal dispersion containing a lecithin and a copolymer gel; and

a therapeutically effective amount of a porcine liver extract in said colloidal dispersion, wherein said porcine liver extract is at a concentration of about 50 mg/ml in said dispersion, and further comprises a heterogeneous polypeptide mixture that is heat stable, insoluble in acetone, soluble in water and is also referred to as Kutapressin, that has been concentrated to substantially remove liquid and then emulsified to form said dispersion, so that said porcine liver extract is present in said transdermal delivery system in concentrated form as a dispersion, and substantially at least 400 mg of the porcine liver extract thereby is topically administered daily.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.