Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-12-27
2001-03-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S487000, C424S489000, C424S449000, C424S484000, C424S501000
Reexamination Certificate
active
06207193
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel transdermal drug delivery system. More particularly, this invention relates to a drug delivery system capable of delivering a drug or therapeutic agent over time epidermally or transdermally through the skin of a human. Even more particularly, this invention relates to a time release, transdermal drug delivery system wherein the active drug or therapeutic agent is encapsulated in a carbohydrate matrix which is, in turn, suspended in a cyanacrylate ester.
BACKGROUND OF THE INVENTION
The use of carbohydrates as carriers for drugs or therapeutic agents is well known. For example, U.S. Pat. No. 3,972,999 to Tsuk discloses miscible melt mixes of amorphous griseofulvin and polyglycolides or lactic acid modified polyglycolides which are formed by heating together the crystalline griseofulvin and the polyglycolide until they melt and form a clear liquid. The liquid is then cooled and subdivided to be incorporated into dosage forms for administration as tablets, capsules, and the like.
U.S. Pat. No. 4,671,953 to Stanley, et. al. discloses a drug dispersed within a carbohydrate mass which is given to a patient to suck on enabling the drug to be released into the patient's mouth as the carbohydrate mass dissolves. The carbohydrates disclosed as useful include sucrose, sorbitol, mannitol or other sweeteners such as aspartanes.
U.S. Pat. No. 4,356,635 to Raman, et. al. discloses a sustained release composition for therapeutic agents formed from a biodegradable, amorphous carbohydrate glass matrix, a hydrophobic substance and a biologically active therapeutic agent. The composition is administered orally or is implanted in an animal where the amorphous carbohydrate glass matrix slowly degrades to release the therapeutic agent. The amorphous carbohydrate component is mixed with an agent to retard its recrystallization. The carbohydrate components that can be used are disaccharides such as sucrose, lactose, maltose or cellobiose and the retarding agents that can be used include polyvinylpyrrolidone, polyethylene glycols, polyvinyl alcohol, maltodextrins, sodium lauryl sulfate, oleyl alcohol, stearyl alcohol, and the like.
U.S. Pat. No. 4,593,824 to Treml, et. al. discloses a homogeneous solution of a glass forming filler material, a biological reagent and water having a viscosity enabling droplets thereof to be dispersed on an inert cryogenic surface and vacuum dried to form a spherical biological reagent that is stable at room temperature and soluble in water. The glass forming filler material is formed from a mixture of a high molecular weight synthetic carbohydrate polymer and a second carbohydrate. The synthetic carbohydrate polymer is used to provide structural integrity and the second carbohydrate is used to provide increased solubility. The high molecular weight synthetic carbohydrate polymer has a molecular weight of at least 10,000 and the second carbohydrate can be melezitose, cellobiose, DEXTRANTO resin, malotriose, maltose, cyclodextran, sorbitol, trehalose, PEG and sucrose.
The use of cyanoacrylates with drugs and therapeutic agents is also known. For example, U.S. Pat. Nos. 4,329,332 and 4,913,908, both to Couvreur, et. al., disclose submicroscopic particles formed from a polymerized alkyl cyanoacrylate containing a biologically active substance. In the '332 patent, the polymerized alkyl cyanoacrylates used contain 1-4 carbon atoms and the submicroscopic particles obtained can be dispensed orally, subcutaneously, intradermally, intramuscularly or intraveneously. The '908 patent discloses that the alkyl can be linear or branched and can contain 1-12 carbon atoms.
In U.S. Pat. No. 5,254,132 to Barley, et. al. there is disclosed cyanoacrylate adhesives which are used as an adjunct covering and closure material in combination with sutures or staples to close surgical openings.
U.S. Pat. No. 5,518,730 to Fuisz discloses obtaining a biodegradable controlled release composition formed by melt-spinning a non-saccharide biodegradable polymer and a bio-effecting agent. The polymers that can be used are any melt-spinnable thermoplastic polymers that are capable of being biodegraded in the body of an animal. The useful polymeric materials include poly(alkyl)cyanoacrylate.
In U.S. Pat. No. 5,753,699 to Greff, et. al. there is disclosed an antimicrobial cyanoacrylate composition which is applied to a non-saturable, superficial wound surface. The cyanoacrylate ester employed polymerizes in situ to form a film over the wound to promote wound healing and protect it against infection.
In U.S. Pat. No. 5,811,091 to Greff, et. al. there is disclosed cyanoacrylate compositions containing a compatible antimicrobial agent, particularly a compatible iodine-containing antimicrobial agent. The compositions polymerize in situ to form a protective antimicrobial polymeric film on mammalian skin.
As can be seen, the foregoing patents disclose various uses of carbohydrates and cyanoacrylates in connection with drug delivery systems or as antimicrobial protective films. None of these patents disclose, much less suggest, the combination of a carbohydrate-containing drug or therapeutic agent carried by a cyanoacrylate ester for use as a time release, transdermal drug delivery system.
BRIEF DESCRIPTION OF THE INVENTION
It has now been found that by encapsulating a drug or therapeutic agent in a carbohydrate and suspending the thusly encapsulated drug or therapeutic agent in a cyanoacrylate ester an effective, time release transdermal drug delivery system is obtained. When applied to the skin of a mammalian, moisture on the skin and skin tissue contact causes the cyanoacrylate ester to polymerize to form a protective coating or seal over the carbohydrate-encapsulated drug or therapeutic agent. Over time, moisture on the skin also dissolves the carbohydrate thereby releasing the drug or therapeutic agent and enabling the drug or therapeutic agent to contact the skin and enter the body system through the pores of the skin.
DETAILED DESCRIPTION OF THE INVENTION
In general, the transdermal drug delivery system of the invention comprises: a drug or therapeutic agent encapsulated in a carbohydrate, said carbohydrate-encapsulated drug or therapeutic agent being suspended in a cyanoacrylate ester.
The drugs or therapeutic agents that can be employed in the drug delivery system of the invention are those that are stable and retain their integrity at elevated temperatures and which are water soluble or are soluble in an aqueous medium. These drugs or therapeutic agents include antibiotics, antivirals, antifungals, antibacterials, analgesics, antiseptics, and the like.
Illustrative antibiotics that can be used are bacitracin, neomycin, chlorohexidine gluconate, erythromycin, polymyxin B and tetracylcine. An illustrative antiviral that can be used is acyclovir. Illustrative antifungals that can be used are ciclopirox, clotrimazole, gentian violet, oxiconazole and penticiclovir. Illustrative antibacterials that can be used are benzalkonium chloride, gentian violet and thimerosal.
Throughout the application and in the appended claims, it should be understood and is intended to be understood that use of the terms “drug”, “drugs”, therapeutic agent” and “therapeutic agents” are interchangeable expressions defining the same or similar entities.
The carbohydrates that can be used in the drug delivery system of the invention are also those that are water soluble or that are soluble in an aqueous medium such as monosaccharides and disaccharides.
Illustrative monosaccharides include those selected from the group consisting of glucose, mannose, galactose and fructose and illustrative disaccharides include those selected from the group consisting of sucrose, lactose, maltose and cellobiose.
The cyanoacrylate esters that can be employed in the drug delivery system of the invention are those that are capable of polymerizing upon contacting moisture. These cyanoacrylate esters have the general formula:
wherein R is an alkyl of 2-12 C atoms, an alkenyl of 5-10 C atoms
Feldman Stephen E.
Ghali Isis
Page Thurman K.
Stephen E. Feldman, P.C.
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