Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-15
2004-01-13
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...
C424S434000, C424S489000, C424S494000, C424S499000
Reexamination Certificate
active
06677346
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations for intranasal administration comprising morphine or pharmaceutically acceptable salt thereof at a pH from about 3.0 to about 7.0. The formulations of the present invention provide enhanced absorption useful for eliciting analgesic or anesthetic responses in mammals.
BACKGROUND OF THE INVENTION
The compound morphine or (−)7,8-didehydro-4,5&agr;-epoxy-17-methylmorphinan-3,6&agr;-diol, is a phenanthrene derivative that exhibits the following general structure:
Structure A (see page before claims)
Morphine is a centrally acting narcotic analgesic that acts as an agonist primarily at mu, kappa and perhaps delta receptors in the central nervous system. By acting on these receptors, morphine causes analgesia and anesthesia as a result of a receptor-mediated central action on pain perception, together with a receptor-medicated modulatory effect on the central transmission of noxious sensation. Some side effects caused by morphine include drowsiness, respiratory depression and euphoria.
Various morphine salts are known in the pharmaceutical arts. For example, morphine sulfate is one of the most commonly prescribed morphine formulations. Other morphine salts such as morphine tartrate and morphine lactate are disclosed in U.S. Pat. No. 5,880,132 issued to Hill and U.S. Pat. No. 5,378,474 to Morella et al. for the treatment and prevention of pain or nociception. Some polar formulations of morphine including morphine-3-glucuronide and morphine-6-glucuronide are disclosed in U.S. Pat. No. 5,629,011 to Illum.
Morphine has been used for a variety of clinical indications. Some examples of such indications include analgesia, for treatment of acute and chronic pain, anesthesia during surgery and to allay anxiety during acute pulmonary edema.
Several delivery routes have been utilized for administering morphine. These routes include oral, injectable, buccal and intranasal administration. For example, oral and injectable morphine sulfate are commonly prescribed for cancer pain. Oral and injectable morphine sulfate are available from Roxane Pharmaceuticals Inc., USA.
Other more desirable delivery routes have been investigated. For example, intranasal delivery of morphine has shown potential for rapid onset and duration of action. Further, intranasal administration offers potential for minimal delays in absorption, is not as invasive as intravenous delivery and achieves therapeutically effective amounts of the drug in plasma For example, intranasal delivery of morphine is disclosed in U.S. Pat. No. 5,629,011 to Illum and U.S. Pat. No. 4,464,378 to Hussain for the treatment of chronic and acute pain. The entire disclosure of U.S. Pat. No. 5,629,011 and U.S. Pat. No. 4,464,378 is herein incorporated by reference.
In considering the intranasal delivery of drugs, the pharmacokinetics thereof are often considered For example, ionization of a drug is believed to directly influence membrane penetration of the drug, and therefore, the absorption potential of the drug into the blood stream. In particular, the ionization of a drug and therefore its absorption potential, is largely determined by the drug's dissociation constant, pK
a
, as well as the pH of the solution in which the drug is dissolved. As reported by Mayersohn in
Modern Pharmaceutics
. Banker & Rhodes, 1979, Ch. 2, Pg. 40, basic compounds are best absorbed from alkaline solutions where pH>pK
a
. Thus, it is generally believed that formulations for delivering basic drugs, in particular intranasal formulations, are best absorbed into the bloodstream when the basic drug is prepared in a formulation solution having a pH above the dissociation constant of the drug. Therefor, a basic drug, such as morphine, would best be absorbed in a basic solution since it would be in its unionized state.
For example, morphine is known to be a basic drug with a pK
a
of about 8. In order to provide effective membrane penetration and absorption through intranasal delivery, heretofore it has been understood that morphine sulfate should be formulated in a basic solution having a formulation pH greater than about 7.0.
Intranasal formulations of morphine sulfate at pH levels below 7.0 would have greater than about 90% of the drug ionized. Such ionization of the drug is believed to lead to poor intranasal absorption. Therefore, several morphine spray formulations are prepared at a pH between 7-8.0. For example, U.S. Pat. No. 5,629,011 to Illum and U.S. Pat. No. 4,464,378 to Hussain disclose morphine formulations for intranasal spray delivery prepared at a pH of 7.2±0.2. These references discuss adding different absorption enhancers to achieve therapeutically effective amounts of morphine upon intranasal administration at such pH range.
Accordingly, efforts have been directed to adding absorption enhancers to intranasal formulations of morphine. Some examples of absorption enhancers include chitosan microspheres, cationic polymers, bioadhesive agents, surface active agents, fatty acids, chelating agents, mucolytic agents and cyclodextrin.
Based on the foregoing, there is a need for morphine formulations that provide enhanced absorption upon intranasal administration. Accordingly, the present invention provides a pharmaceutical formulation for intranasal administration comprising morphine or pharmaceutically acceptable salt thereof at a pH from about 3.0 to about 7.0. Such formulations provide therapeutically effective amounts of morphine for eliciting analgesic and anesthetic responses.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical formulation for intranasal administration comprising morphine or pharmaceutically acceptable salt thereof at a pH from about 3.0 to about 7.0.
In one embodiment, the present invention provides a method for eliciting an analgesic or anesthetic response in a mammal comprising nasally administering a therapeutically effective amount of morphine or pharmaceutically acceptable salt thereof at a pH from about 3.0 to about 7.0.
In yet another embodiment, the present invention provides a method for eliciting an analgesic or anesthetic response in a mammal comprising nasally administering a therapeutically effective amount of morphine or pharmaceutically acceptable salt thereof at a pH from about 3.0 to about 7.0 to the mammal in combination with a nasal delivery system.
REFERENCES:
patent: 4464378 (1984-08-01), Hussain
patent: 5202128 (1993-04-01), Morella et al.
patent: 5629011 (1997-05-01), Illum
patent: 5756483 (1998-05-01), Merkus
patent: 5880132 (1999-03-01), Hill
patent: 5942251 (1999-08-01), Merkus
patent: WO 82/03768 (1982-11-01), None
The Merck Index (Twelfth Edition), p. 1074-1075.*
The Merck Index (Twelfth Edition), p. 126.*
“Current and Practical Compounding Information for the Pharmacist: Compounding Nasal Preparations”, 1998, Paddocklabs Inc., www.paddocklabs.com.*
Banker et al.,Modern Pharmaceutics, Ch. 2, p. 40 (1979).
Achari Raja G.
Behl Charanjit R.
deMeireles Jorge C.
Dua Ramneik
Romeo Vincent D.
Fay Zohreh
Graybeal Jackson Haley LLP
Kwon Brian-Yong S.
Nastech Pharmaceutical Company Inc.
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