Title:  Nicotine-containing pharmaceutical compositions giving a rapid transmucosal absorption

United States Patent:  6,676,959

Issued:  January 13, 2004

Inventors:  Andersson; Sven Borje (Od.ang.kra, SE); Landh; Tomas (Lund, SE); Jonn; Stefan (Helsingborg, SE); Gruden; Stefan (Rydeback, SE); Lindberg; Nils-Olof (Malmo, SE)

Assignee:  Pharmacia AB (Helsingborg, SE)

Appl. No.:  856522

Filed:  July 11, 2001

PCT Filed:  November 4, 1999

PCT NO:  PCT/SE99/01983

PCT PUB.NO.:  WO00/30641

PCT PUB. Date:  June 2, 2000

Abstract

Formulations of nicotine for use in nicotine replacement therapy. The formulations are intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa. The formulations essentially comprise apolar, polar and surface-active components. The formulations may be administered in combination with other nicotine formulations.

SUMMARY OF THE INVENTION

Compositions for the therapeutic delivery of nicotine are provided. Said compositions comprising nicotine provide rapid transmucosal absorption of nicotine. The compositions are preferably used for therapeutic administration of nicotine. The compositions are, preferably, applicable to, but not restricted to the buccal administration route.

The meaning of "disintegration" as used in the description and in the claims denotes melting, solubilization, erosion or a combinatorial effect of these physical changes of the invention.

The meaning of "melting point range" as used in the description and in the claims refers to the gradual decrease of the amount of solid, semisolid or amorphous material, as opposed to liquid material, as the temperature is increased.

The meaning of increase in "frequency", as measured as the heart beat frequency (rate), as an indirect measure of nicotine absorption is used in the description and in the claims as detailed by Armitage ("Blood levels of nicotine and cotinine attained during smoking" in: The Workshop on Nicotine, Nov. 11-13, 1974, Stockholm, Sweden) and Schievelbein ("Nicotine, Resorption and Fate" in Intl. Encyclop. Pharmacol. Therapeut. 1984, 114, 1). These references show that a rapid increase in plasma nicotine levels is associated with an increase in arterial blood pressure and heart rate.

"Adhesiveness" is readily appreciated, by those skilled in the art, to be a consequence of the behavior of the formulation in question in the environment of the site of application with which it is striving to approach uniformity in the sense of thermodynamics and mass transport. Adhesiveness is achieved through the driving force to reach close apposition caused by the formulation's thermodynamic degree of freedom followed by the establishment of non-covalent interaction to the surface or site of application.

DETAILED DESCRIPTION OF THE INVENTION

It is the primary object of the present invention to provide a tobacco supplement or a tobacco substitute, for use in e.g. smoking cessation and nicotine replacement therapies which provide the user with a satisfactory dose of nicotine so as to reduce tobacco withdrawal symptoms without causing an unacceptable local irritation. More specifically it is the object of the invention to provide such a nicotine containing tablet, for transmucosal, preferably buccal, delivery, which disintegrates and/or melts at body temperature with or without the aid of salivary fluid or mechanical erosion, or a combination thereof after which the formulation shows adhesiveness towards the body tissue in the oral cavity.

Further objects of the invention will become apparent to one skilled in the art, and still other objects will become apparent hereinafter.

According to the invention nicotine is provided in an apolar-polar vehicle chiefly comprising fat, carbohydrate and/or polyols, and a surface-active substance.

Pharmaceutically acceptable apolar components according to the invention include in the broadest sense of the invention any lipid (oil, fat, or wax) such as

cocoa butter and cocoa butter alternatives (including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR), cocoa butter improvers (CBI) (Minifie, B. Chocolate, Cocoa, and Confectionery: Science and Technology, 2^nd ed, 1980, p 80-88. AVI Publ. Comp., Inc, Westport, Conn., USA and in G. Talbot, Vegetable fate, In S. T. Beckett (Ed): Industrial Chocolate Manufacture and Use, 2^nd ed., 1994, p 242-257, Chapman & Hall, London),

coconut, palmkernel oil, and other similar oils characterized by being predominantly based on lauric and myristic acids,

corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils characterized by primarily being based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point,

fish oil, tallow, lard, butterfat, and other animal derived fats, and

synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using no acidic, alkaline or enzyme catalysis.

The above mentioned fats can be used as single components or mixed with each other; they can be either crude or refined using physical or alkaline refining. They can also be subjected to further processing including catalytic hydrogenation, interesterification, transesterification and fractionation.

Preferably said apolar components produce alone or in mixture with other components of the invention, a formulation of the invention which exhibit a melting point ranging from about 25^oC. to about 45^oC., preferably from about 33^oC. to about 45^oC. with or without the addition of polar solvent or body fluid such as salivary fluid.

Especially useful are edible and pharmaceutically acceptable vegetable fats with a fatty acid composition chiefly being based on C14:0, C16:0, C18:0, C18:1 and C18:2, most useful those being rich in C16 and C18, and any combination thereof having melting point ranging between from about 25^oC. to about 45^oC., preferably from about 30^oC. to about 45^oC. Especially preferable are vegetable fats in particular, tempering or non-tempering fats including CBA's including CBE's, CBR's, CBS's and CBI's known to those skilled in the art which in formulation with other components of the invention exhibit a disintegration time at body temperature, with or without the addition of polar solvent or body fluid such as salivary fluid, which is less than 45 minutes, preferably less than 10 minutes.

Pharmaceutically acceptable carbohydrates as components according to the invention include sucrose, fructose, glucose, galactose and invert sugar.

Pharmaceutically acceptable polyols as components according to the invention include sugar alcohols and mixtures thereof, e.g. xylitol, sorbitol, maltitol, mannitol, isomalt and glycerol. It is readily appreciated by those skilled in the art that synthetic polymers of sugar alcohols and/or carbohydrates, such as polydextrose can comprise in whole or in part the polar component of the invention.

Pharmaceutically acceptable surface-active agents as components of the invention include nonionic, ionic, preferable anionic, and zwittterionic surfactants or mixtures, fractions or derivatives thereof.

Suitable compounds in the group of nonionic surface-active agents include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, mono- and diglycerides and esters thereof other than specifically mentioned, polyoxyethylene stearates, polyglycerolesters of fatty acids (including polyglycerolpolyricinoleic acid (PGPR)), and sorbitan fatty acid esters.

Anionic surface-active agents as components of the invention include fatty acids and their soaps, lactylates, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate, and latanol.

Suitable compounds in the group of zwitterionic surface-active agents include zwitterionic phospholipids, such as phosphatidylcholine and phosphatidylethanolamine. Most preferable are edible pharmaceutically acceptable mixtures of surface-active agents such as soyalecithin and/or egg lecithin and fractions or derivatives thereof As realized by those skilled in the art compatible combinations of surface-active agents are included without departing from the spirit of the invention.

Furthermore, as readily appreciated by those skilled in the art, additives for controlling the behavior of the melting point range, texture, integrity, consistency and moulding properties of the formulation can be incorporated in the invention without departing from the spirit of the invention. It is also readily appreciated by those skilled in the art that thickening agents and agents added to increase colloidal stability are incorporated in the invention.

In addition usually employed pharmaceutical excipients and/or food additives such as flavoring agents, buffering agents, preservatives and such components can be added without departing from the spirit and scope of the invention.

It is, furthermore, appreciated by those skilled in the art that conventional variations of product design such as tablets being solid moulded with center filling or center additions, drops, and coated variations thereof fall within the scope of the invention.

It is, furthermore, appreciated by those skilled in the art that the method of manufacturing depends chiefly on the choice of apolar and polar composition. Therefore variations of methods of manufacturing of the invention and equipment used therefore falls within the scope of the invention. This includes methods and processes of temperature treatment and techniques for particle size reduction.

The embodiments, practice and methods of manufacturing the compositions of this invention is further illustrated by the following non-limiting examples:

EXAMPLE 1

CBR Bases

The influence of nicotine on the melting point range of commercially available cocoa butter replacers was determined using differential scanning calorimetry (DSC Perkin Elmer with scanning rate at 2.5^oC.). Analyses were performed on samples containing four different CBR's (Akopol E, Akoprime E (a hydrogenated vegetable oil type II NF 18), Akomel S and Akocote RT, all of Karlshamns Sweden AB) with melting point (mp ^oC.) and fatty acid composition according to the manufacturer--see below Table 1.

To the CBR's were added different amounts of nicotine (0, 1, 2, 4 and 6 mg/g). Additional analyses were performed on Akomel S with 12 mg/g nicotine.

No significant difference in onset temperature and peak temperature for any of the CBR's at any of the levels of nicotine was observed as compared to those stated by the manufacturer and as compared to samples without nicotine addition. This indicates that the melting point range of the CBR's is not significantly influenced by the addition of nicotine.

One week storage at 5^oC., 20^oC. and 30^oC. of Akopol E with 2 mg/g nicotine does not significantly influence the melting point range as indicated by the onset and peak temperature determined by DSC. Similar results were obtained with Akoprime E with 2 mg/g nicotine analyzed after temperature cycling (5^oC.-40^oC., 40^oC.-5^oC.).

Formulations containing 2 mg/g nicotine in mixtures of 90.7 Akoprime E and 9.1 weight % lecithin (Epicuron.RTM. 200, Lucas Meyer, Germany), did not show any significant difference in melting point range as compared to 0 mg/g nicotine level. Addition of lecithin caused a significantly reduced variation between samples. Addition of 10 weight % sucrose or 10 weight % xylitol and with concentrations of 1-6 mg/g nicotine did not show any significant difference in melting point range as compared to 0 mg/g nicotine level.

EXAMPLE 2

Fatty Base Witepsol.RTM.

50 g of commercially available suppository base Witepsol.RTM. H15 (Huls AG, Germany) with an open-tube melting point range of 33.5^oC.-35.5^oC. was melted. Portions of 0.5 g were moulded in blisters made of a copolymer of acrylonitrile and methyl acrylate (Barex.RTM.) and cooled. 2 or 4 mg pure nicotine was added to each blister whereafter an additional amount of 0.4 g of melted fatty base was added.

EXAMPLE 3

Cocoa Butter Base

Batches of 20, 30, 35 and 40 g respectively of cocoa butter were melted and kept at 40^oC. To the melts 10, 15, 20 and 30 g respectively of icing sugar was added whereafter the melts were homogenized. Subsequently, 0.125 mg of pure nicotine was added to each batch. Pieces of 0.8 g from the melts were moulded in blisters.

A part of the lipid is melted. The solid components are added and mixed. A reduction of particle size of the solid components is performed by milling in a roll-refiner. If the solid components have already got the required particle size, e g by milling before the mixing with the lipid, roll-refining is dispensed with. After treatment in the roll-refiner the mixture is remelted and mixed with the rest of the lipid, which is also melted. A mixing of the melt, so called conching, is performed in a suitable mixer. Emulsifier and nicotine is added. Tablets or other solid dosage forms are subsequently made using suitable techniques, such as moulding, extrusion, congealing, including pastillation, or compacting, when necessary after suitable preconditioning.

Claim 1 of 89 Claims

What is claimed is:

1. A nicotine-containing pharmaceutical composition being devoid of polyethylene glycol, comprising one or more cocoa butter or cocoa butter alternatives present in the amount of 5%-90% by weight, one or more polar components present in the amount of 1%-70% by weight, and one or more surface-active components present in the amount of 0.01%-30% by weight, and optionally pharmacologically acceptable excipients, and wherein said composition provides transmucosal absorption of nicotine.

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