Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-04-22
2002-05-14
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S357000
Reexamination Certificate
active
06387880
ABSTRACT:
FIELD OF THE INVENTION
The present invention is for pharmaceutical compositions for transdermal delivery of N-[N-[5-[4-(aminoiminomethyl)phenyl-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine or its esters and their pharmaceutically acceptable salts which are useful as platelet aggregation inhibitors.
BACKGROUND OF THE INVENTION
N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine which is represented by the following formula
or its esters and their pharmaceutically acceptable salts are known to be useful as platelet aggregation inhibitors. See International Publication W092/15607, published Sep. 17, 1992.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gpIIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
Initially, N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine or its esters and their pharmaceutically acceptable salts were administered orally, parenterally, rectally or by inhalation spray. See International Publication W092/15607, published Sep. 17, 1992.
These prior conventional methods of administering drugs to patients, however, possess certain shortcomings.
The oral route of drug administration, for example, is inadequate for several reasons, even if the drug is administered to the patient at periodic intervals according to a well-defined schedule.
The rate of absorption of drug through the gastrointestinal tract is affected by both the contents in the tract and the passage of time as the drug travels through the small intestine. Therefore, such variables as whether the drug is administered before or after eating, and the type and quantity of food eaten, for example, high or low fat content, or whether the drug is administered before or after bowel movement, affect the rate of absorption of the drug which takes place in the small intestine.
Additionally, the time of passage of drug through the small intestine is affected by the rate of peristaltic contraction, adding further uncertainty.
Also important is the rate of circulation of blood to the small intestine, and the fact that many drugs administered by this route are rendered inactive by gastric acid, digestive enzymes of the gastrointestinal tract, or by liver, where the drug can be metabolized to an inactive product.
These factors make it difficult to achieve a desired time course of concentration of drug in the blood.
The most inevitable result of the oral administration of drugs through the gastrointestinal tract is that the level of drug in circulation surges to a peak level shortly after the time of drug administration, followed by a decline in drug concentration in the blood and body compartments.
The administration of drugs by injection likewise entails certain disadvantages. For example, very strict asepsis must be maintained in order to avoid infection of the blood, the vascular system and the heart. Drug administration by poor intravenous technique may result in perivascular injection, when that was not intended. The typical result of injection of a drug into the blood is a sudden rise in the blood concentration of the drug followed by an uncontrollable decline in drug concentration. Additionally, administration of drugs by injection is inconvenient and painful.
Other dosage forms for systemic administration of drugs, such as rectal suppositories and sublingual lozenges, also produce non-uniform levels of the therapeutic agent in circulation. These dosage forms require great patient cooperation and have low patient acceptability, resulting in decreased patient compliance with a prescribed drug regimen, which is the most common failure of drug therapy.
The present invention is a new form of administration of N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine or its esters and their pharmaceutically acceptable salts into a transdermal pharmaceutical composition to achieve blood levels which are effective in the inhibition of platelet aggregation. Particularly interesting compounds which are representative of this above-described class of compounds are exemplified by
N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine, hydrochloride;
N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine, diethyl ester;
N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine, dimethyl ester; and
N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine, acetate.
Transdermal delivery of N-[N-[5-[4-(aminoiminomethyl)-phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine or its esters and their pharmaceutically acceptable salts offers advantages over the other methods of delivery which were discussed above. An advantage is the ease of application over the intravenous or intramuscular delivery. This convenience of use offers the benefit of a lifestyle uninterrupted by hospital visits, which are needed when administering by other known methods. Administration by IV or intramuscular delivery has certain disadvantages of inadvertent needle sticks. Needle sticks have also been associated with the risk of secondary systemic infections. Transdermal delivery does provide the ability to deliver drugs directly to general circulation. Effective transdermal delivery affords a controlled, constant, zero-order release of active compound. Transdermal delivery is greatly advantageous in that it can be used in pediatric age groups, where IV or IM dosing is very difficult.
Another advantage of transdermal delivery is that the delivery of the active can be rapidly terminated by removing the patch. Other routes of delivery do not possess this most desirable advantage.
Recognizing that the outer layer of the skin, the epidermis, protects the area under the skin from penetration of foreign chemicals, various enhancing agents have been used to deliver drugs transdermally. Substances that help promote drug diffusion through the stratum corneum and epidermis are referred to as skin-penetration enhancers, accelerants, adjuvants and absorption promoters. B. Idson,
Cosmetics
&
Toiletries
, 95, 59 (1980) states that the factors affecting drug penetration and consequently in most cases, effectiveness, are complex. The vehicle that provides ideal conditions for one drug may prove unsatisfactory for another.
Various penetration enhancers are known to be useful in transdermal drug delivery. U.S. Pat. No. 4,863,970, U.S. Pat. No. 4,722,941, U.S. Pat. No. 4,931,283 and EP 351,897 disclose some representative penetration enhancers used in transdermal compositions and for topical administration.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical formulation in the form of a transdermal delivery system comprised of N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine or its esters and their pharmaceutically acceptable salts and a delivery solvent. Effective delivery solvents for the practice of this invention are exemplified by ethanol and n-methyl pyrrolidone.
It is the primary object of this invention to provide a pharmaceutical composition for transdermal delivery of N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-&agr;-aspartyl]-L-phenylalanine or its esters and their pharmaceutically acceptable salts.
Feigen Larry P.
Griffin Martin John
G.D. Searle & Co.
Weddington Kevin E.
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