Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2000-08-24
2002-03-05
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S731000
Reexamination Certificate
active
06353029
ABSTRACT:
BACKGROUND OF THE INVENTION
Presently, there is no adequate dermatological treatment for hyperpigmentary disorders, such as solar lentigines, melasma and post-inflammatory hyperpigmentation. The depigmentation market is currently serviced by marginally effective prescription and over-the-counter (“OTC”) products.
The principal active in OTC products is hydroquinone. It is employed at a level of 1.5% or 2%.
Prescription strength hydroquinone dermatological products contain 3% or 4% hydroquinone. Such products are irritating to the skin and can cause irreversible depigmentation. Thus there is great need for a safe and effective treatment for hyperpigmentary disorders.
Nair et al U.S. Pat. No. 5,194,247, discloses a corticosteroid free synergistic depigmentation composition containing 0.1% to 5%, by weight, 4-hydroxyanisole (“4-HA”) and 0 001% to 1%, by weight, of at least one retinoid selected from all-trans retinoic acid, (N-acetyl-4-aminophenyl) retinoate and 11-cis, 13-cis-12-hydroxymethyl retinoic acid-&Dgr;-lactone.
Nair et al U.S. Pat. No. 5,470,567, discloses a corticosteroid free synergistic composition for skin depigmentation. The composition comprises 0. 1% to 2%, by weight, 4-HA and a retinoid. The retinoid is 0.001% to 0.1%, by weight, all-trans retinoic acid; 0.001% to 0.01%, by weight, (N-acetyl-4-aminophenyl) retinoate or 0.001% to 0.1% by weight 11-cis, 13-cis-12-hydroxymethyl retinoic acid-&Dgr;-lactone.
Thus, the prior art appreciates the use of 4-HA and all-trans retinoic acid in treating hyperpigmentary disorders. All-trans retinoic acid is also known as Vitamin A acid and as Tretinoin. It is henceforth referred to herein as“Tretinoin”.
U.S. Pat. No. 5,470,567, discloses testing of a solution of 1% 4-HA and 0.01% tretinoin in 98.99% PEG-8/ethanol (5:95) (see Column 6, lines 36-43). The solution was obviously freshly prepared and tested immediately thereafter. Patentees do not teach or even suggest that such solution would provide long term storage stability of tretinoin and 4-HA contained therein.
Assuming that the ethanol employed by patentees was ethanol USP (containing 5% water), patentees' composition containing 98.99% of a 5:95 mixture of PEG-8 and ethanol, respectively, would have contained 4.7% water, an amount insufficient to solubilize other formulation ingredients found necessary by the present inventors to enable long-term storage stability of solutions containing 4-HA and tretinoin.
It should be noted that patentees in U.S. Pat. No. 5,470,567 and 5,194,247 fail to appreciate that 4-HA, in the presence of emulsifiers, degrades tretinoin contained in emulsion formations or that a 4-HA and tretinoin solution containing at least 12%, preferably at least 15%, more preferably at least 20% water, as in the present invention, will afford long-term stability of the tretinoin and 4-HA components.
Kligman et al U.S. Pat. No. 6,008,254 discloses a method of treating skin disorders with high-strength tretinoin. Patentees disclose a composition in which tretinoin is carried in a solvent vehicle. Patentees teach that Tretinoin is substantially insoluble in aqueous vehicles and therefore organic solvent vehicles are preferred. Patentees indicate that a preferred vehicle comprises from about 20 to 80%, by weight, ethanol or isopropanol with the balance being liquid glycol, preferably polyethylene glycol. The Examples illustrate a 0.25%, by weight, solution of tretinoin in a 50:50 mixture of 95% ethanol/polyethylene glycol 400.
SUMMARY OF THE INVENTION
The object of the present invention was to develop a composition comprising a solution of tretinoin and 4-HA having long term physical and chemical stability (viz. long term storage stability), as hereinafter defined, and optimal skin permeation, said composition being useful in the topical treatment of solar lentigines and related hyperpigmented lesions.
Tretinoin is known to be a very unstable drug. It can undergo thermal, oxidative and photo degradation. Because of its instability, the United States Pharmacopoeia allows up to a 35% overage for commercial 0.05% tretinoin solution formulations marketed in the United States. The British Pharmacopoeia allows a 20% overage for tretinoin solution and commercial tretinoin products in Europe are available in 0.025, 0.05, 0.1 and 0.2% strengths.
Compared to tretinoin, 4-HA is more stable, however, it can still undergo oxidative decomposition to hydroquinone and other degradation products.
Oxidation and photochemical reactions are, for the most part, one-electron reactions. Trace amounts of environmental agents can powerfully catalyze these reactions. Contamination by trace metal ions can catalyze oxidative reactions by many orders of magnitude. Even the presence of trace amounts of photosensitive agents in the excipients can cause a susceptible molecule, such as tretinoin, to undergo apparent photochemical reactions.
Oxidative degradation reactions are free radical reactions. Characteristically, many free radical reactions involve lag time or lag phase corresponding to gradual build-up of free radicals via the initial step. If the radicals produced from the initiator go into a propagative cycle, the overall loss of a drug, like tretinoin, will then follow first-order decay with respect to the drug. If chain branching occurs, as it the case of drugs containing conjugated double bonds, the overall loss of drug will be many orders of magnitude and the drug will have a very short shelf life.
Oxidative degradation kinetics involves lag time. Since, oxygen solubility in solvents, such as water and alcohol, is temperature dependent, the interpretation of temperature effects on oxidative reactions is not predictable.
The complications involved in oxidative degradation kinetics make it difficult to rely on accelerated stability data to evaluate the shelf like of tretinoin.
Tretinoin is known to undergo antioxidation. Various degradation products are produced, for example, epoxides, dioxetane, an endoperoxide and double-bond cleavage products. The oxidation process may also result in isomerization (Motto, M. G. et al, J. Chromat., 48, 1989, pages 255-262).
In general, retinoids are known to isomerize by chemical methods, with heat, and, most importantly, by the action of light.
Theoretically, each of the double bonds in retinoic acid can undergo isomerization to give mono, cis, and multiple cis isomers, resulting in a possible total of sixteen double bond isomers. Eight additional isomers are possible due to cyclization of the 7-cis isomer of retinoic acid. Thus a total of twenty four photoisomers is possible.
The chemical stability of 0.05% tretinoin in solution and gel formulations is reported in the literature (see British Pharmacopoeia, II, 1993, page 1137).
The shelf life of tretinoin in a propylene glycol-alcohol solution at 25° C is 6.7 months. In an aqueous tretinoin gel with lauromacragol (Brig® 35s) as the solubilizing agent, the shelf like is twelve days. The shelf life of tretinoin in aqueous gels, with and without Cremophor® RH40 as a solubilizing agent, is 3 months and 10 months respectively. The stability of tretinoin is low in solubilized formulations and is influenced by the types of solubilizing agents and other excipients used in the formulations (Brisaert, M. G., et al, Pharma. Acta. Helv., 70, 1995, pages 161-166).
In an effort to develop a pharmaceutically elegant dermatological composition containing tretinoin and 4-HA and having long term storage stability (as hereinafter defined), the present inventors incorporated the tretinoin and 4-HA in cream compositions. The oil-in-water emulsion based creams broke. Most likely, this was due to the 4-HA component as it is soluble in both the oil phase and water phase. Addition of other emulsifiers and thickeners resolved the problem of physical instability of the emulsion; however, tretinoin proved to be very unstable in such formulations.
DESCRIPTION OF THE PREFERRED EMBODIMENT OF THE INVENTION
The long-term storage stable composition of the present invention comprises:
(a) 0.5 to 5% (w/v), preferably 1 to 3% (w
Bristol--Myers Squibb Company
Jarvis William R. A.
Kim Vickie
O'Brien Maureen P.
Zeller Charles J.
LandOfFree
Storage stable tretinoin and 4-hydroxyanisole containing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Storage stable tretinoin and 4-hydroxyanisole containing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Storage stable tretinoin and 4-hydroxyanisole containing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2864840