Drug – bio-affecting and body treating compositions – Anesthetic – local
Reexamination Certificate
1999-11-03
2001-09-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Anesthetic, local
C514S330000
Reexamination Certificate
active
06284805
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a new drug formulation, and in particular to bags, ampoules or other containers including a sterile drug solution.
BACKGROUND OF THE INVENTION
Many drugs are provided in aqueous solution. For this purpose, they are typically packaged, in a glass, plastics or other container such as an ampoule, vial or bag, and sterilised by autoclaving. They can then be stored and used as necessary.
One class of drugs that is administered as a solution, e.g. by injection or infusion, comprises the long-acting local anesthetics which include an amine. Particular examples of this type of therapeutic agent are 1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamides, of which specific examples are mepivacaine, ropivacaine, bupivacaine and levobupivacaine. These drugs are usually provided as the hydrochloride salt.
Jones et al, Am. J. Hosp. Path. 50(11):2364-5 (1993), reports that there were no significant changes in assay or pH upon storage of bupivacaine in polypropylene syringes.
Similarly, Upton etat, Aus. J. Hosp. Pharm. 17(4): 267-70 (1987), demonstrated no adsorption of bupivacaine to a range of plastics inducing polypropylene.
Hampe Da Poian et al, Revista Brasileira de Anestesiologia 33(1):23-5 (1983), reported no significant changes in pH or stability of solutions of bupivacaine (0.25%, 0.5%, 0.75%) following sterilisation in glass ampoules.
Chem. Abs. 97(25):222883 (1982) indicates that solutions of bupivacaine in vials were stable to heat and light following sterilisation.
U.S. Pat. No. 5,505,922 discloses a combination of a local anesthetic and lithium ions, to provide enhanced anesthetic activity. The lithium ions are described as a buffer. Among various possible additional components, it is suggested that pH buffers may be used to establish a physiologically compatible pH range and to enhance the solubility of the anesthetic.
SUMMARY OF THE INVENTION
The present invention is based on the identification of a problem associated with the provision of sterile aqueous solutions of an acid addition salt of such carboxamide therapeutic agents, in a plastics container, on the discovery of a reason for this problem, and also on a solution to it. The problem is that autoclaving causes a reduction in pH, and this may make the formulation more acidic than is suitable for the intended use, particularly if a narrow pH range has been specified, for regulatory purposes. As shown by the evidence presented below, the problem is caused by adsorption of the free base by the plastics, with the release of acid. This problem is solved by the use of a buffer.
DESCRIPTION OF THE INVENTION
The problem that is addressed by the present invention has been observed, and will be described with reference to these materials by way of illustration only, when the material of the container is polypropylene and the therapeutic agent is levobupivacaine hydrochloride salt. Polypropylene is often preferred for use in ampoules, vials or bags, e.g. of the type intended for infusion, but the invention may be equally applicable to other plastics materials, including other polyolefin polymers and copolymers.
The pKa of levobupivacaine is about 8.2 at 25° C. Typically, a solution of levobupivacaine.HCl has a pH of 5-5.5. On autoclaving in polypropylene ampoules, a pH drop is observed. It has been found that a small amount (about 1%) of free base is adsorbed by the polypropylene during the autoclave cycle of an unbuffered solution, and that adsorption in buffered solutions increases with pH. Thus, for example, buffer strength from 5 to 250 mM at pH 6 gives 30-40% adsorption, while buffering at 10 mM, pH 4, gave no pH change and limitation adsorption to 0.2%.
The theory behind these observations is that the pKa of the amine group in levobupivacaine drops as the temperature increases during the autoclaving cycle, providing free base in solution The hydrophobic free base is adsorbed by the polypropylene, leaving residual HCl in solution, causing reduction of the pH. This reduction itself causes reprotonation of the remaining free base in solution, limiting the adsorption. In buffered systems of sufficient strength, the acid is removed by the buffer, and the pH is maintained; in turn, this gives a constant salt:free base ratio. This ratio will be of the order of 100:1 at 2 pH limit below the pKa, and may be of the order of 50:50 at a pH equal to the pKa. This ratio determines the amount of adsorption.
For the carboxamide-type anesthetic agents that are used in this invention, especial benefit may be seen when its concentration in solution is relatively high, e.g. at least 0.75% w/v. At such a concentration, the pH drop observed on autoclaving is relatively great. However, a desire effect may be seen at lower concentrations, e.g. 0.25 or 0.5% w/w.
Any suitable buffer may be used, and in particular a salt formed between a weak acid and a strong base. Typical examples of such buffers are alkaline metal citrates, lactates and acetates. The amount of buffer that is required can be very small, e.g. 5 to 100 mM.
Typically, the acid forming the acid addition salt of the carboamide is different from that forming the buffer. It is preferably a hydrohalide salt, and most preferably the hydrochloride.
REFERENCES:
patent: 4474751 (1984-10-01), Haslam et al.
patent: 5505922 (1996-04-01), Thut et al.
patent: 5736127 (1998-04-01), Stoy et al.
patent: 5932597 (1999-08-01), Brown
Jones, Jerry W. et al. (1993) “Stability of bupivacaine hydrochloride in polypropylene syringes”Am J Hosp Pharm50:2364-2365.
Upton, Richard N. et al. (1987) “The Relationship Between Some Physicochemical Properties of Ionisable Drugs and their Sorption into Medical Plastics”Aust J Hosp Pharm17(4):267-270.
Da Poiam, Sergio Hampe et al. (1983) “Adrenalina, Esterilizacao, pH e Dissociacao dos Anestesicos Locais”Revista Brasileira de Anestesiologia33(1):23-25.
Liang, Jin et al. (1982) “Preparation of bupivacaine injection and its physicochemical properties”Chem. Abs.97(25):222883.
Darwin Discovery Ltd.
Fubara Blessing
Page Thurman K.
Saliwanchik Lloyd & Saliwanchik
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