Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-07-01
2002-04-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S400000, C424S444000, C514S938000, C514S969000, C514S871000, C514S825000
Reexamination Certificate
active
06368618
ABSTRACT:
BACKGROUND OF THE INVENTION
Rheumatoid arthritis and related conditions are some of the most prevalent diseases throughout the world. In the U.S., over 30 million patients suffer from these debilitating diseases which are characterized by painful and swollen joints due to inflammation in the musculoskeletal tissues of the joints. Over the course of the disease, thickening of the synovial membranes and deformity of the afflicted joints can develop. Although etiology of the disease is unknown, changes in autoimmune functions in genetically susceptible individuals have been often implicated as the primary cause of the disease.
For many decades, non-steroidal anti-inflammatory drugs (NSAIDs) have played an important role in treating these diseases. Among the many NSAIDs which have been introduced, ibuprofen has become one of the most widely used due to its proven efficacy and low cost. Ibuprofen is highly effective for the treatment of many types of inflammatory and arthritic diseases such as rheumatoid arthritis, arthralgia, tendinitis, gout, ankylosing spondylitis, and other related conditions. Due to its potent analgesic and antipyretic activities, ibuprofen is also effective for relief of pain and fever, and is commonly used to relieve muscle ache, neuralgia, dysmenorrhea, headache, and fever.
Oral administration of many NSAIDs, including ibuprofen, can cause serious adverse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. Therefore, in an effort to minimize the adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years. Transdermal delivery, in particular, is an attractive option because it avoids the hepatic first-pass metabolism, reduces the side effects associated with oral administration, is associated with higher patient compliance and, in some cases, enhances therapeutic efficacy of the drug.
Although topical administration of certain NSAIDs, such as naproxen, ketoprofen, diclofenac, piroxicam and ibuprofen has been shown to deliver the drug to the local musculoskeletal tissues of joints where arthritic conditions often develop, there is much need to improve efficacy of topically applied NSAIDs. The effectiveness of topical administration of many NSAIDs is limited by the inability of these drugs to permeate the skin. The lack of clinical activity of topical NSAIDs in the treatment of rheumatoid diseases has been attributed to insufficient permeation of the drug through the stratum corneum, the major barrier of the skin towards entry of foreign chemicals. Indeed, among the many factors that potentially affect drug permeation across the skin from topical/transdermal formulations, diffusion of the drug from the vehicle toward the skin surface and subsequent partitioning into the stratum corneum are of particular importance. Some of the approaches that have been used to improve the dermal permeation of drugs are to increase lipophilicity of the drug, to incorporate the drug into lipid vesicles such as liposomes and to employ a permeation enhancer in the formulation. Despite the clear advantages of topical/transdermal therapy as opposed to systemic therapy, the absence of effective transdermal formulations of NSAIDs in the marketplace indicates that efforts directed toward improving the delivery system are extremely important for these drugs.
In most conventional topical formulations of NSAIDs that are commercially available, the active ingredients are simply dissolved, dispersed or otherwise formulated in a suitable pharmaceutical vehicle. The thermodynamic activity of the drug in such formulations is relatively low due to the limited solubility of drugs in the vehicle. For example, in the conventional pharmaceutical creams which are often used as a vehicle for topical delivery, the drug is first dissolved in an oil and then emulsified. For example, in U.S. Pat. No. 5,318,960 (Toppo, issued Jun. 7, 1994) it was disclosed that an ibuprofen-containing composition was formulated by admixing an oil surfactant with an amount of the drug, then adding alcohol and water to obtain an oily dispersion that can be further formulated for improved transdermal delivery. However, the use of a quantity of oil to dissolve the drug dilutes drug concentration in the topical preparation and thus reduces the thermodynamic activity of the active ingredient in the vehicle, the primary driving force for percutaneous absorption. In addition, the limited amount of drug that is dissolved in the oil phase has to diffuse through the surrounding inert oil layer in order to reach the skin surface prior to absorption. Diffusion through the inert oil can be the rate-limiting step in the partitioning of drugs to the skin.
Moreover, some conventional topical formulations containing high amounts of ibuprofen and long chain polymers as solubilizers are unstable, as ibuprofen can react with long chain polymers and has a tendency to crystallize on storage. In an effort to improve the stability of topical pharmaceutical compositions containing ibuprofen, WO 91/04733 (Smith et al.) discloses a eutectic mixture (oily melt) of ibuprofen and menthol, which is formulated into a topical gel containing 3-4%, by weight, of ibuprofen. However, depending on the relative proportion of menthol and ibuprofen, one or both may be present partially in microcrystalline form. In addition, the thermodynamic activity of ibuprofen in the oil phase is relatively low due to the presence of large amounts of menthol (up to 50%).
Stott et al. examined other eutectic systems for transdermal delivery of ibuprofen and found that a binary system consisting of 40:60 ibuprofen:thymol (w/w) showed a eutectic melting point of 32° C., which is about the same as the skin temperature used for their permeation studies (
J. Controlled Release
, 50: 297-308 (1998)). However, any composition of ibuprofen:thymol, other than the 40:60 eutectic mixture, was a two phase system with some of the component remaining as solid. Mixtures containing ibuprofen and L-menthol showed a eutectic melting point of 19° C. at 30:70 ibuprofen:L-menthol (w/w), and compositions containing ibuprofen in a ratio of 40:60 were liquid at 32° C. Similarly, mixtures containing ibuprofen and LD-menthol showed a eutectic melting point of 13° C. at 25:75 ibuprofen:LD-menthol (w/w). Thus, the only binary mixtures potentially suitable for topical formulations of ibuprofen as an oily melt were those having very narrow compositional ranges and containing relatively low amounts of ibuprofen. The permeability through human epidermal membranes was enhanced when ibuprofen was delivered by way of a eutectic formulation. The largest flux increase at 32° C. was obtained from ibuprofen:thymol mixtures at the weight ratios that included the eutectic compositions (35:65 and 40:60, w/w). Notably, increased flux was not observed for saturated ibuprofen:thymol mixtures above 40:60, w/w. On the other hand, maximum fluxes for the ibuprofen:menthol mixtures were observed for mixtures containing ibuprofen in concentrations high enough (e.g., 50:50 ibuprofen:LD-menthol, w/w) to contain some solid at 32° C., analogous to a saturated solution. The authors warn, however, that if the amount of ibuprofen is further increased, the system becomes “too solid” and difficult to apply to the membrane.
Chemically, ibuprofen is a-methyl-4-(2-methylpropyl) benzene-acetic acid. It has one chiral center, thus there are two enantiomers, S(+)-ibuprofen and R(−)-ibuprofen, also known as S-ibuprofen and R-ibuprofen. The racemic form consisting of equal amounts of S(+)-ibuprofen and R(−)-ibuprofen is exclusively used in presently available commercial preparations. Racemic ibuprofen a high melting point (about 78° C.), while both stereoisomers of ibuprofen, S(+)-ibuprofen and R(−)-ibuprofen, melt at 44° C. All these forms are poorly soluble in water. And, although ibuprofen is a lipophilic drug, it does n
Jun H. Won
Kang Lisheng
Ghali Isis
Mueting Raasch & Gebhardt, P.A.
Page Thurman K.
Sandberg Victoria A.
The University of Georgia Research Foundation Inc.
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