Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-29
2003-05-06
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S282000
Reexamination Certificate
active
06559154
ABSTRACT:
FIELD OF INVENTION
The present invention relates to pharmaceutical compositions comprising at least one sodium channel blocking compound in a suitable pharmaceutical vehicle.
BACKGROUND OF THE INVENTION
The methods and compositions of the present invention provide a solution that meets the requirements for clinical use. The formulation can be administered systemically for indications including, but not limited to, pain requiring analgesia and treatment of drug dependence (See, U.S. Pat. No. 5,846,975). The formulation can be administered as described in A Method of Analgesia, Dong Q. et al, U.S. patent application Ser. No. 09/695,053, filed Oct. 25, 2000, Attorney Docket No. 3519-0103P.
Tetrodotoxin is a nonprotein neurotoxin with potent activity. It is found in diverse animal species, including puffer fish, goby fish, newt, frogs and the blue-ringed octopus.
As sodium channel blocking compounds with high selectivity, tetrodotoxin and saxitoxin specifically bind to a site on an extracellular region, either an SS1 region or an SS2 region, of a sodium channel alpha subunit. Surprisingly, compounds binding the SS1 or SS2 region of a sodium channel can produce long-acting and potent analgesia or anesthesia with no severe adverse effects (Dong Q. et al, supra, and Ku B. et al, U.S. patent application Ser. No. 09/702,826, filed Nov. 1, 2000, Attorney Docket No. 3519-0106P).
Tetrodotoxin (TTX) has a chemical formula of C
11
H
17
N
3
O
8
, and has a molecular weight of 319.28. The Merck Index, 10
th
Ed. (1983), states tetrodotoxin is the generic name for the compound octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-(1,3)dioxocino(6,5-d)-pyrimidine-4,7,10,11, 12-pentol, which has the following structure:
The TTX molecule consists of a perhydroquinozoline group with a guanidine and six hydroxyls. Pure TTX is a white crystalline powder, odorless and tasteless. It turns black around 220° C. without decomposition. TTX is soluble in acidic aqueous solution, but is not soluble in organic solvents. The pKa (aqueous) of TTX is 8.76. Thus TTX is a basic alkaloid. Aqueous solution of strong acids can decompose TTX, so usually TTX is dissolved in an aqueous solution of a weak organic acid. TTX is relatively thermally stable in neutral to weakly acidic solutions, but will be destroyed promptly in a strongly acidic or basic aqueous solution.
The present invention utilizes tetrodotoxin having a purity of at least 96% as the primary drug substance. Tetrodotoxin can be obtained by the technology described in A Method of Extracting Tetrodotoxin, Zhou M. et al, U.S. patent application Ser. No. 09/695,711, filed Oct. 25, 2000, Attorney Docket No. 3519-0101P. Further purification of TTX is described in Chinese patent application no.00132673.2, filed Nov. 22, 2000 and in U.S. patent application Ser. No. 09/818,863, filed Mar. 28, 2001, Attorney Docket No. 3519-0110P.
Analogs of tetrodotoxin can be used in the formulation of the invention. Preferred analogs of TTX are anhydrotetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin and tetrodonic acid.
Because TTX decomposes readily in gastric acid, oral ingestion is not considered to be a favored route of administration. Therefore, the compositions of the present invention are mainly for injection, preferably intramuscular injection. Most injectable formulations are solutions, and such properties as solubility, stability and safety of the drug must be considered when designing an injection (Bi D., Pharmaceutics, 4
th
Edition).
The calculation of the dose of TTX for injection is based upon the results of pre-clinical pharmacology and pharmacodynamics studies. The calculation of the clinical pharmaceutical dosage is based upon the dosage effective in animals. In general, it is calculated as ⅕ of the effective animal dosage. 50, 60, and 70 kg are used as human body weights, respectively.
The TTX analgesic ID
50
(half inhibition dosage) in the acetic acid-induced twisting test in mice is 2.80 &mgr;g/kg (intramuscularly, IM). Accordingly, the recommended clinical dosage for humans is:
2.80
&mgr;g/kg×
(⅕)×50 (60, 70)
kg=
28.0 (33.6, 39.2)&mgr;g
The TTX effective dosage in the formalin-induced inflammation test in rats is 2.5 &mgr;g/mg (IM) (P<0.01). Accordingly, the recommended clinical dosage for humans is:
2.50
&mgr;g/kg×
(⅕)×50 (60, 70)
kg=
25.0 (30.0, 35.0)&mgr;g
It is also possible to calculate the initial clinical dosage based upon LD
50
value. Considering the results of pharmacodynamics studies, the clinical dosage can be calculated as {fraction (1/50)} of the LD
50
. 50, 60, and 70 kg are used as human body weights, respectively. Our most recent study shows that the LD
50
in mice is 11.1 &mgr;g/kg (im), therefore, the suggested clinical dose is:
11.1
&mgr;g/kg×
1/50×50(60,70)
kg=
11.1(13.32,15.54)&mgr;g
Based upon the results of pharmacology studies and knowledge in the art, the concentration of TTX for injection is designed to be 15 &mgr;g/mL, and the fill of a TTX injection is typically 1 or 2 mL.
TTX is a perhydroquinozoline compound that is only slightly soluble in water but soluble in an aqueous solution having an acidic or basic pH. Therefore, such commonly used auxiliary solvents as dilute acetic acid, hydrochloric acid and citric acid can be used dissolve TTX for formulation. Maintaining an acidic pH helps ensure the stability of a TTX formulation, as TTX is rather stable in weakly acidic solutions. The acid is preferably a weak organic acid, and formic acid, acetic acid or propionic acid is preferred.
It is preferable to include an adequate buffer, such as an acetate buffer, a citrate buffer, a phosphate buffer or a borate buffer, for the purpose of maintaining the pH of the formulation in an acceptable range. We have found (See Example 1) that the pH of a TTX formulation should be kept between 3.5-7.0, more preferably between 3.5-5.0. The buffer can be added in an amount of up to 0.5% by weight of the formulation. (A density of 1 g/ml is assumed for the formulated product.) As an example, a mixture of 55.5 ml of a 0.2M acetic acid solution and 4.5 ml of a 0.2M sodium acetate solution can be made, then added to a formulation in an amount of up to 5% by volume of the formulation. In this example, the buffer will constitute about 0.06% by weight of the formulation. Thus, the buffer can typically constitute about 0.1% by weight of the formulation.
In addition, a mixed solvent consisting of a glycol, preferably a C
2
-C
6
alkane glycol, most preferably propylene glycol, and water is also desirable for improving the stability of TTX in a formulation. Addition of the glycol to the formulation results in acceptable stability with use of higher pH, providing a formulation that is more tolerated by the patient upon injection.
Environmental factors, such as temperature, light, humidity, and oxygen, were studied to determine their influence on the stability of TTX formulation so that a formulation and manufacturing technology that meet quality requirements can be devised. Test results (See Example 4) demonstrate that humidity and light have no significant effect on a TTX formulation, but increasing temperature will cause the content of TTX to decline. Therefore, a TTX formulation should be stored at low temperature so as to ensure its stability.
More components may be added to a TTX formulation in consideration of improving performance and convenience of storage, including viscosity increasing agents such as polyvinyl alcohol, celluloses, such as hydroxypropyl methyl cellulose and carbomer; preservatives, such as benzalkonium chloride, chlorobutanol, phenylmercuric acetate and phenyl mercuric nitrate; tonicity adjusters, such as sodium chloride, mannitol and glycerine; and penetration enhancers, such as glycols, oleic acid, alkyl amines and the like. A vasoconstrictor can also be added to the formulation. Combination formulations including the long-acting sodium channel blocking compound and an antibiotic, a steroidal or
Kang Yuhong
Shum Frank Hay Kong
Birch & Stewart Kolasch & Birch, LLP
Fay Zohreh
Kwon Brian-Yong
Nanning Maple Leaf Pharmaceutical Co., Ltd.
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