Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
1999-04-19
2001-07-03
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S550000, C554S156000, C530S847000, C514S177000, C514S784000, C514S946000, C514S947000, C424S550000, C424S551000, C424S553000
Reexamination Certificate
active
06255502
ABSTRACT:
This application is a 371 of PCT/GB97/01873 filed Jul. 11, 1997.
BACKGROUND OF THE INVENTION
This invention relates to a pharmaceutical composition formulated for transdermal or transmucosal delivery which contains as an active ingredient an acid addition salt of a basic drug and a fatty acid or bile acid, and to certain novel acid addition salts of basic drugs and fatty acids or bile acids.
The oral route of drug delivery is well established as the most preferred route of drug administration. However, when administered by the oral route a drug enters the gastrointestinal tract where many therapeutic agents are subjected to extensive presystemic elimination by gastrointestinal degradation and/or hepatic metabolism resulting in erratic or poor bioavailability. Further disadvantages of the oral route are difficulty in swallowing medications especially by the elderly or in paediatrics, or in the presence of nausea and vomiting.
Delivery of drugs via the oral, nasal, ocular, rectal or vaginal mucosae or via the skin, offers a means of avoiding the disadvantages of the oral route as the drug reaches the systemic circulation directly. The mucosal route of drug delivery is a useful alternative to parenteral delivery where rapid therapeutic effect is desired. The transermal route is advantageous for sustained release of active ingredients.
There are several methods known in the art to deliver drugs to the oral and nasal mucosae [see Chien, Y W ed. Novel Drug Delivery Systems, 2nd Edition, Marcel Dekker 1992, pp 183-188, 244-249]. These include buccal and sublingual tablets or lozenges, adhesive patches, gels, solutions or sprays (powder, liquid or aerosol) for the oral cavity and solutions or sprays (powder, liquid or aerosol) for the nasal cavity. Suppositories and pessaries are well known galenical forms for rectal and vaginal delivery, and sterile solutions, suspensions and ointments are similarly well established forms for ocular delivery [The Pharmaceutical Codex 12th Edition, The Pharmaceutical Press; Remington's Pharmaceutical Sciences 18th Edition, Mack Publishing Company]. Transdermal drug delivery has been extensively reviewed [Osborne, D W and Amann, A. Topical Drug Delivery Formulations, Marcel Dekker Inc.].
Relatively few drugs are currently administered via the mucosal and dermal routes due to problems associated with poor transport of the drugs across mucosal or dermal membranes. A given drug will partition between the lipid phase and the aqueous phase of biological membranes according to the lipophile/hydrophile balance of the drug molecule. According to pH partition theory, the permeation of an ionisable substance through biological membranes is dependent on the concentration of the unionised species. Basic drugs, depending on their pKa, are generally ionized to varying extents at the pH of the mucosal surface, resulting in poor transmembrane permeation.
The absorption of drugs from biological membranes may be enhanced by (i) increasing drug solubility, (ii) pH modification to favour the unionized form of the drug, (iii) addition of bioadhesive agents to improve contact between the delivery system and the membrane and (iv) incorporation of so-called penetration enhancers.
There are a number of penetration enhancers known to influence the permeability of drugs across biological membranes [for a recent review see Walker, R B and Smith, E W Advanced Drug Delivery Reviews 1996, 18, 295-301].
The mechanism by which sodium salts of medium chain fatty acids (C
6
, C
8
, C
10
and C
12
) enhance the absorption of hydrophilic drugs across intestinal mucosa has been studied [Lindmark, T et al, J. Pharmacol. Exp. Ther. 1995, 275(2), 958-964.].
Oral absorption of antibiotics in U.S. Pat. No. 5,318,781 to Hoffmann-La Roche is claimed to be enhanced by use of salts (e.g sodium) of capric or caprylic acids together with an anionic surfactant.
Transdermal formulations containing absorption accelerators teaching the use of lauric acid diethanolamide salt is claimed in JP 05185371 to Sekisui Chemical Company Limited.
The effects of sodium salts of bile acids, caprylic or capric acids as nasal drug absorption promoters have been reported. [Yamamoto, A et al Int. J. Pharm. 1993, 93(1-3), 91-99.].
Colonic absorption of cefmetazole and inulin are reported to be increased by the use of sodium caprate, sodium laurate, and mixed micelles composed of sodium oleate and sodium taurocholate [Tomita, M. et al, Pharm. Res. 1988, 5(6), 341-346.].
The promoting effect of sodium caprylate, sodium caprate and sodium laurate on rat nasal absorption of insulin has been reported [Mishima, M et al, J. Pharmacobio-Dyn 1987, 10(11), 624-631.].
WO 9524197 to Sekisui Chemical Company Limited, Japan; Dainippon Pharmaceutical Company Limited teaches a percutaneously absorbable plaster composed of a support and, formed on one side thereof, a pressure-sensitive adhesive layer comprising a pressure-sensitive adhesive, a drug and a percutaneous absorption accelerator.
Skin penetration enhancement using free base and acid addition salt combinations of active agents are described in EP 321870 to Theratech Inc. Compositions for topical application were prepared containing active pharmaceutical permeants capable of existing in both free base and acid addition salt form. The acids used included HCl, tartrate, sulphate, HBr, mesylate and maleate.
A fatty acid salt of propranolol as an alternative to polymeric formulations was investigated for possible use in sustained-release oral formulations and evaluated in dogs. An increase in bioavailability was observed after propranolol laurate was administered. [Aungst, B J; Hussain, M A, Pharm. Res. 1992,9(11), 1507-9.].
In an article in J. Pharm. Sci (1990), 79(12), 1065-1071 by T Ogiso and M Shintani the effects of a series of fatty acids including lauric acid and myristic acid on the percutaneous absorption of propranolol was examined. The results indicate that a significant proportion of propranolol will penetrate across the stratum corneum by forming a complex with a fatty acid, and that the complex will dissociate to each component in the interface between the corneum and a viable epidermis, where propranolol partitions into this water-rich tissue.
In an article in Chem. Pharm. Bull. (1991), 39 (10), 2657-2661 by T Ogiso et al, there is reported that propranolol suppositories with lauric acid at various molar ratios were administered to the rat rectum. Propranolol absorption from Witespol and macrogol suppositories with lauric acid at a 1:1 molar ratio was much larger than that after propranolol alone. The results supported the concept that a portion of propranolol, by forming a 1:1 complex with lauric acid, would penetrate across the rectal mucosa more easily than propranolol alone.
In an article in Pharm. Res. (1989), 6(7), 628-632 by P G Green et al, it is disclosed that the lipophilicity of cationic drugs can be increased by forming ion pairs with the carboxylate anion of fatty acids. Transport of cations across an iso-Pr myristate membrane was facilitated in the presence of oleic acid, and lauric acid, providing an appropriate pH gradient existed.
Slowly dissolving albuterol salts prepared with adipic and stearic acids have been investigated as a potential means of extending the duration of action of the drug following aerosol delivery to the lung [Jashnani, R et al, J. Pharm. Sci. 1993, 82(6), 613-16.].
From the above prior art it is evident that enhancement of penetration of active agents through the skin, intestinal, oral, nasal or rectal mucosa has been effected by incorporation of fatty acids or bile acids present as the free acid or usually as the sodium salt at a given concentration in a pharmaceutical composition containing an active agent, present as free acid or free base, or as a simple pharmaceutically acceptable salt. Little attention has been paid to means of manipulating the active agents per se to attain enhanced penetration through the membrane bar
De Kock Luéta-Ann
Penkler Lawrence John
Whittaker Darryl Vanstone
Carr Deborah D.
Farmarc Nederland B.V.
Pillsbury & Winthrop LLP
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