Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-10-31
2004-09-14
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S023000, C514S027000, C514S046000, C536S028600, C536S028700, C536S029100
Reexamination Certificate
active
06790837
ABSTRACT:
The present invention pertains to the field of liquid pharmaceutical formulations, and more particularly to syrup formulations containing ribavirin that have improved taste and stability.
Ribavirin is known to be useful in the treatment of hepatitis C as well as various other disease states. Ribavirin, 1&bgr;-D ribofuranosyl-1H-1,2,4 triazole 3-carboxamide, also known as Rebetol® in capsule form, or Virazole® in inhalable form, available from Schering Corporation, Kenilworth, N.J. and ICN Pharmaceuticals, Inc., Costa Mesa, Calif., respectively, is described in the Merck Index, compound No. 8199, Eleventh Edition. See also U.S. Pat. No. 4,211,771.
Certain patient populations exist that have difficulty in swallowing tablets or capsules. One common example of such a population is children. One solution to overcome the difficulty of administering certain medicaments is to provide the medicaments in a liquid formulation, e.g., in solution, emulsion, suspension or extract form. These liquid formulations are advantageous because they are easy to administer, and typically have organoleptic properties that make the formulation more palatable to the patient.
Syrup formulations are commonly used for delivery of pharmacological agents. Traditional syrups are concentrated solutions of sugar (generally sucrose) in purified water, such as Syrup, NF prepared with 850 grams sucrose and sufficient water to make 1000 mL according to the procedure given in the official monograph at page 1990 of NF XVII The National Formulary, United States Pharmacopeial Convention, Inc., Rockville, Md. U.S.A., 1990. As is well appreciated in the art, syrups frequently are flavored, such as with fruit or mint flavors, usually for purposes of masking an unpleasant taste caused by the presence of a dissolved or suspended pharmacologically active substance. A pleasant taste is particularly important when the formulation is intended for ingestion by children.
Due to the typically high sugar content in syrups, syrups are susceptible to microbial infestation. Syrups frequently must contain antimicrobial components to ensure safe storage without the proliferation of pathogenic molds, yeasts, bacteria and the like; a typical antimicrobial deemed suitable for use in foods and other ingestable substances is sodium benzoate.
A prime concern with any liquid formulation is the stability of the active ingredient, both short term and over time. In general, drug substances are less stable in aqueous media than in the solid dosage form. Thus, it is important to properly stabilize and preserve those formulations, especially if the formulation contains water. Chemical reactions can take place in these products that may involve ingredient-ingredient interaction. Another potential reaction is a container-product interaction that may alter pH, and thus, if the active ingredient is pH sensitive, instability in the form of precipitates or degradation products could result. Ribavirin is one such active ingredient that is pH sensitive, and it is readily degraded by hydrolysis when in a liquid formulation.
Prior art syrup formulations have been marketed by ICN that contain ribavirin as an active ingredient. These formulations, however, have certain disadvantages with regards to long term stability as compared to the syrups of the present invention. Ribavirin is readily degraded by hydrolysis in these formulations. Moreover, a solution pH that promotes hydrolysis will, in turn, affect ribavirin degradation directly by increasing the amount of ribavirin hydrolysis. Additionally, ribavirin stability is compromised when there is an increase in the formation of reducing agents in the formulation, i.e., the sugar sucrose can be hydrolyzed to the reducing sugars fructose and glucose. These sugars can in turn increase the hydrolysis of ribavirin. Accordingly, it is desired to provide a storage-stable liquid formulation of ribavirin that has an improved stability over time and is safe for ingestion by patients.
SUMMARY OF THE INVENTION
The present invention provides a liquid formulation comprising ribavirin, a buffering system, wherein the pH of the liquid formulation is in the range of about 4.8 to about 5.3, at least one pharmaceutically acceptable sweetening agent, and at least one pharmaceutically acceptable viscosity increasing agent.
The present invention also provides a pharmaceutically acceptable syrup formulation comprising ribavirin, a buffering system, wherein the pH of the pharmaceutically acceptable syrup formulation is in the range of about 4.8 to about 5.3, at least one pharmaceutically acceptable sweetening agent, and at least pharmaceutically acceptable one viscosity increasing agent.
The present invention also provides a pharmaceutically acceptable syrup formulation comprising ribavirin, a buffering system, said buffering system comprising sodium citrate dihydrate and citric acid anhydrous, wherein the pH of the pharmaceutically acceptable syrup formulation is in the range of about 4.8 to about 5.3, at least one pharmaceutically acceptable sweetening agent, and at least pharmaceutically acceptable one viscosity increasing agent.
REFERENCES:
patent: 4211771 (1980-07-01), Witkowski
patent: 4880784 (1989-11-01), Robins et al.
patent: 4968606 (1990-11-01), Yokozeki et al.
patent: 5767097 (1998-06-01), Tam
patent: 6423695 (2002-07-01), Tam et al.
patent: WO99/62516 (1999-12-01), None
PCT International Search Report, PCT/US02/34898 dated Jan. 31, 2003.
Patent Abstracts of Japan, Vo. 008, No. 034 (C-210) 58198416 A, Nov. 18, 1983.
Rebetol Package Insert, 2001.
Heimbecher Susan K.
Sequeira Joel A.
Barts Samuel
Lewis Patrick
Lipka Robert J.
Schering Corporation
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