CA2163089A1 - Nasal drug delivery composition containing nicotine - Google Patents
Nasal drug delivery composition containing nicotineInfo
- Publication number
- CA2163089A1 CA2163089A1 CA002163089A CA2163089A CA2163089A1 CA 2163089 A1 CA2163089 A1 CA 2163089A1 CA 002163089 A CA002163089 A CA 002163089A CA 2163089 A CA2163089 A CA 2163089A CA 2163089 A1 CA2163089 A1 CA 2163089A1
- Authority
- CA
- Canada
- Prior art keywords
- nicotine
- ion
- exchange
- microspheres
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Abstract
The present invention provides a nasal drug delivery composition comprising nicotine or a pharmacologically-acceptable salt or derivative thereof wherein the composition is adapted to delivery a pulse of nicotine for rapid absorption and a controlled release of nicotine for subsequent sustained absorption. The controlled release phase can be achieved by providing an ion-exchange material which will form a complex with the nicotine. The ion-exchange material may be a polymeric material such as a polysaccharide, or may be in the form of bioadhesive ion-exchange microspheres. The pulse release can be achieved by overloading the ion-exchange material with nicotine so that the composition contains some excess nicotine forimmediate release and absorption. Alternatively, some nicotine may be associatedwith a non ion-exchange material which will release the nicotine immediately on contact with the nasal mucosa, for example non-ion-exchange bioadhesive microspheres.
Description
WO 94127~76 PCT/GB94/01092 , 2~ ~3~8~
NASAL DRUG DELIVERY COMPOSITION CONTAINING NICOTINE ~
The present invention relates to compositions for nasal ~(lmini~tration and, more particularly, to compositions for nasal ~lmini~tration of nicotine.
5 Smoking remains the single most i",po.~ant preventable cause of death in modern society. It can be estimated that in the US alone more than 430 000 deaths in 1988 were attributable to cigarette smoking. At least nine out of ten smokers are to some extend depen~lerlt upon nicotine and 75% are moderately to strongly dependent and continue smoking 10 despite attempts to stop. In the United States the strong interest in stopping smoking is demonstrated by the fact that nearly 20 million peopLe try to quit smoking each year. Their need for ~ ition~l help can Ibe seen in the fact that more than 90% fail to m~int~in their ~hsti~lence.
15 The Imajor problem with nicotine is that it is highly addictive. Nicotine fulfils all criteria of an addictive drug, it is psychoactive, it affects the mood, it can act as a primary reinforcer, it induces tolerance, and physical as well as psychological changes occur on withdrawal.
Importantly, there is no direct evidence that nicotine itself is 20 carcinogenic or mutagenic, nor does it act as a tumour initiator, promoter or co-carcinogen. Similarly, none of the major metabolites of nicoline are known to be carcinogenic. In contrast, tobacco and especially tobacco smoke contains several potent carcinogens.
A mlajor limiting factor in the successful use of nicotine replacement 25 therapy for smoking cessation is the lack of an appro~,l,ate delivery WO 94/27~76 PCT/GB94/01092 ~ 6~g.a~ 2 system. When a person smokes a cigarette, the level of nicotine rise rapidly in the blood and in the brain with an interval of just 10-20 seconds between taking a puff and the nicotine arriving in the brain. The presently marketed nicotine replacement products, the transdermal nicotine patch 5 and the nicotine chewing gum, are not entirely s~ti~f~ctory in that they do not provide the patient with the nicotine "buzz" associated with smoking a cigarette, since they are both slowly acting controlled release systems where only low nicotine plasma levels are obtained. Hence clinical trails have shown that only about 20% - 30% of those smokers who have used 10 nicotine p~tches and nicotine chewing gum successfully quit smoking after one year compared to lS % of those smokers receiving behavioural support alone.
Transdermal patches seem to be no more effective than placebo in m~int~ining smoking cessation in the long term. The long term results lS after the use of patches alone have not been impressive Medical letter (Vol. 34, p37, 1992).
The nicotine chewing gum is a slow release preparation where the rate of release of nicotine will depend on the rate of chewing. It takes 20-30 min of vigorous chewing to release 95% of the nicotine content of the gum.
20 Without chewing or if the gum is accidently swallowed negligible amounts of nicotine are released. The gum contains 2 or 4 mg of nicotine. A
typical smoker needs about IS pieces of gum a day. The gum has an unpleasant taste and may be irritating to the mouth and throat. Potential side effects are heartburn and hiccups. Tired and aching jaws may be 25 experienced from intensive chewing and users rarely m~int~in blood nicotine concentrations above one third of their levels from smoking. The chewing gum is contraindicated in individuals with gastritis or active peptic ulcer di~e~ce and presents difficulties for those wearing dentures.
WO 94127576 PCTtGB94/01092 ~I630g~
US 3877468, US 3901248 and US 3845217 discloses a chewing gum comprising nicotine in the form of a complex with an insoluble cation-exchange base.
The nicotine patch placed on the skin will give a steady release of nicotine 5 over 24 hours and should be changed daily. The patch is available in three sizes delivery about 21, 14 and 7 mg/24 hours) With the patch in place it takes 3 - 4 hours to attain significant blood levels of nicotine. The continuous dosing provided by p~tches can disrupt the usual day/night variation in nicotine intake provided by smoking and can result in a total 10 dose of nicotine per 24 hour exceeding the normal smoking dose.
Moreover it seems that if nicotine is given both night and day con.l,ar~d to only daytime, sleep disturbances and nightmares can result. A potential side effect of the patch is skin irritation. A further disadvantage with the nicotine patch is that it is a passive system and for some individuals, a 15 closer involvement with the treatment is to be preferred.
Thus, neither the nicotine patch system nor the nicotine chewing gum system can be considered to be satisfactory for nicotine replacement thera~py and smoking cessation.
It is well established that nicotine is easily absorbed nasally. Nicotine 20 concentrations in the blood of regular users of dry snuff are similar to those of cigarette smokers and peak concentrations after a single pinch of snuff is reached in a time similar to that for smoking a cigarette. The absolute bioavailability of nicotine applied to different nasal regions has been measured by Johansson et al. (1991) in man. Single doses of 1 mg 25 were given and plasma concentrations followed over 6 hours.
Bioavailability, as compared to IV infusion was 60 to 7~%. The rate of absorption was fast. the maximum concentration being reached within WO 94/27!;76 PCT/GB94/01092 g~ 4 about 10 minutes. No differences could be found for different nasal treatments.
Nasal sprays containing nicotine have been suggested as an alternative approach for smoking cessation. The prior art has described various devices for the better delivery of nicotine. For example WO 8703813 a spray device with an electronic timer restricting doses to a predetermined number per session is described. A nasal aerosol spray supplying nicotine for anti-smoking therapy is mentioned as an advantage. In US 4655231 an improved snuff for nasal application of nicotine cont~ining a pure nicotine salt, a water soluble diluent and colouring and flavouring is described. The water soluble diluent is preferably an organic acid. The Ini~lulc allows rapid application of nicotine. GB 2133691 describes an aqueous solution of nicotine or a non-toxic salt of nicotine together with a non-irritating thickening agent. The composition has a pH of 2-6 and has a viscosity of at least 100 CP. The thirkçrling agent is a natural or synthetic polymer or an oil substance comprising the oil phase of an emulsion. A nicotine solution with a viscosity less than 100 CP has been mentioned in RD 239015. WO 9l/09599 discloses a smoking substitute for sublingual administration comprising a nicotine-cyclodextrin complex.
The composition is stated to have improved stability and taste, pH
independent release and reduced irritant sensation. It is also suggested that the composition could be given nasally.
The nasal nicotine systems discussed above were designed to give rapid absorption of nicotine, followed by a rapid decrease in the level of absorbed nicotine, mimicking the effect of smoking a cigarette. More recently, Sutherland et al. 1992, suggested that the rapid absorption of the nicotine when given nasally may be an important factor for smokers for whom other forms of replacements are too slow. Although nasal nicotine -- 21~3~
spray systems will provide the desired "buzz" effect, the benefit is short lived and will necessitate frequent dosing. This will be unacceptable to the potential user.
The pharmacokinetics of nicotine in man has been described in some detail 5 (for eY~ample see Benowitz 1990). The importance of including features associated with tolerance has been stressed. For example in the end of the day the response of the cigarette is blunted owing to the development of tolerance. Tolerance can develop and regress in cycles throughout the day. Rec~use of dose response and tolerance characteristics, habitual 10 smokers need to smoke at least lS cigarettes and consume 20-40 mg of nicotine per day to achieve the desired effect of cigarette smoking and to minimi~e withdrawal discomfort. The dose of systemically available nicotine absorbed by regular smokers averages about 1 mg per cigarette.
The daily nicotine intake of smokers averages about 25 mg. Two rninutes lS after the first cigarette the plasma nicotine level reaches about 13 ~g/l.
The nicotine peak plasma levels of regular smokers of lS or more cigarettes per day average about 35 ,ug/l during daytime.
We have now found that an improved nicotine replacement formulation can be achieved by providing a nasal composition which provides both an 20 initiall rapid release and absorption of nicotine, a pulse effect, followed by a controlled release and absorption of nicotine to provide a sustained high level of absorbed nicotine. The invention therefore provides a nasal drug delivery composition comprising nicotine or a pharmacologically acceptable salt or derivative thereof in which the nicotine or nicotine salt 25 or derivative is released as a pulse followed by a controlled release phase.
The pulse effect provides an initial rapid peak in plasma nicotine levels whiclh gives the "buzz" effect of smoking a cigarette. The controlled release phase then provides a more gradually increased and maintained ~G~ 6 high plasma level of nicotine, removing the craving for further nicotine, and avoiding the need to use the composition at frequent intervals.
The controlled release effect can be achieved by providing an ion-exchange material in the composition. By ion-exchange material we mean S a natural or synthetic material comprising ionisable groups and which have the ability to exchange ions attracted to their ionised groups with ions of the same charge present in solution. Nicotine is a basic drug and when ionised it carries a positive charge. The ion-exchange material must therefore be one which when ionised releases a positive ion leaving a 10 negative charge to which the ionised nicotine is attracted. The ion-excll~nge material forms a complex with the ionised nicotine and releases the nicotine slowly when in contact with the nasal mucosa.
The ion-exchange capacity of the ion-exchange material used should preferably be in the range 0.01-50 milli equivalents/g, more preferably 15 0.1-20 meq/g and most preferably 0.2-10 meq/g.
The ion-exchange material is preferably bio~(lhesive to aid its retention in the nasal cavity. By bioadhesive we mean a material which will adhere to the surface of the nasal cavity. The ion-exchange material gradually releases nicotine providing a controlled release and uptake of nicotine 20 across the nasal mucosa.
Natural or synthetic nicotine may be used or a pharmacologically-acceptable salt or derivative of nicotine. Nicotine forms water soluble salts and double salts with many metals and acids. The use of salt forms of nicotine avoids the problems associated with the free base form of 25 nicotine includes losses due to volatility and decomposition in the presence of oxygen. Preferred salts for use in the invention includes nicotine WO 94/27576 21 6 3 0 ~ ~ PCT/GB94/01092 dihydrogen tartrate, nicotine tartrate, nicotine hydrochloride, nicotine oxalaee, nicotine hydrogen tartrate, nicotine dihydrochloride, nicotine sulphate, 2-methyl nicotine and other nicotine derivatives. Nicotine dihydrogen tartrate or nicotine tartrate are especially preferred and also 2-5 methyl nicotine which has reduced side-effects on the heart. Unless otherwise stated, all amounts of nicotine stated are calcnl~t~d as the equivalent amount of nicotine free base.
The pulse release of nicotine may be achieved by providing a material which is not an ion-exchange material. The nicotine associated with this 10 mater;al will then be released immedi~tely on contact with the nasal mucosa for rapid absorption. Alternatively, excess nicotine is provided in the composition so that the ion-exchange material is overloaded with nicotine. The excess nicotine not bound by the ion-exchange material is available for immediate uptake on contact with the nasal mucosa. This 15 excess nicotine is also referred to throughout as "free nicotine".
Monovalent cations can also be included in the composition to compete with the nicotine for binding with the ion-exchange material, thus ensuring that some of the nicotine is left as free nicotine. Such cations should be non-toxic and pharmacologically acceptable, for example sodium, calcium 20 and ammonium.
The ion-exchange material may be in the form of bioadhesive microspheres, or may be an aqueous solution, suspension or freeze-dried preparation of a polymeric material.
It has previously been shown that bioadhesive microspheres are ab!e to 25 incre,ase the residence time of a formulation in the nasal cavity thereby increasing the time available for absorption of the drug (Illum et al, 1987).
a~ 8 It was also shown by Illum et al. (1988) that such a system was able to increase the absorption of the antibiotic agent, Gentamicin thereby allowing it to be given via the nasal route rather than by injection.
The use of the bioadhesive microspheres in drug delivery compositions for S transmucosal ~dministration has been described in WO 88/09163 and WO 89/03207.
The slow release of drugs and model compounds from ion-exch~nge microspheres has been the subject of previous work (Illum and Davis, 1982, US Patent 4847091). Here the strong binding of the drug to the 10 miclospheres via a process of ionic interaction has been used to modify drug release rates. The applications described were for pa~ e,~l ~ministration and the local administration of an anionic drug sodium cromoglycate to the nasal cavity. Various ion-exchange microsphere systems are described in the prior art (for example see Kown et al. (1990), 15 Cremers et al (1990) and Codde et al (1990)). None of these systems has been used nasally for nicotine administration.
The ion-exchange microspheres suitable for use in the present invention are microspheres which carry suitable anionic groups such as carboxylic acid resitlues, carboxymethyl groups, sulphopropyl groups and 20 methylsulphonate groups. Carboxylated starch microspheres are especially preferred. Other materials include hyaluronic acid, chondroitin slllrh~te, ~lgin~t5, heparin and heparin-albumin conjugates, as described in Kwon et al. (1991) albumin-poly (cY-L glutamic acid), albumin-poly (aspartic acid) or ion-exchange albumin microcapsules as described by Savaya et al 25 (1987). Ion-exchange resins (cation exchangers) can also be used such as Aminex-A-6 (Biorad)-a resin containing sulphonate groups or those with carboxymethyl or sulphopropyl groups. Cation exchanges which can be 9 2163-3~879 used include carboxymethyl dextran (CM SephadexlM) and sulphopropyl dextran (SP SephadexrM) carboxymethyl agarose (CM Sepharose~M), carboxymethyl cellulose, cellulose phosphate, sulphoxyethyl cellulose, agarose (Sepharose), cellulose beads (Sephacel) and dextran beads S (.Seph~dex) (all available from Pharmacia) are materials which such functional groups. Carboxylated starch microspheres (Cadexomer) are available from Perstorp.
Cation exchangers on polystyrene include the Amberlite and Dowex strongly acidic cation exchangers and the Amberlite weekly acidic cation 10 exchangers as described in the Sigma Chemical Co Ltd catalogue, 1993, plS91-1593. The Amberlite strongly acidic cation exch~n~ers have sulphonic acid functional groups and the weakly acidic ones have carboxylic acid functional groups. The Dowex exchanger has nl-clç~r sulphonic acid functional groups.
15 The ion-exchange microspheres can be used with free nicotine to provide both the fast pulse release of nicotine and the controlled release, or can be mixed with non-ion-exchange microsphere. Nicotine is adsorbed to the surface of the non-ion-exchange microsphere and will be released quickly on contact with the nasal mucosa to provide the pulsed effect. Suitable 20 materlals for use as non-ion-exchange microspheres include starch, gelatine, collagen and albumin. When a mixture of ion exchange and non-ion-exchange microspheres are used, the composition should contain between 50:1 and 1:1 of ion-exchange to non-ion-exchange microspheres, preferably 25:1 to 5:1 and more preferably 10:1.
25 The term microsphere as used herein is defined as substantially spherical particles which can be a monolithic solid sphere or in the form of a small capsule. To ensure correct deposition in the nasal cavity, the 3Q8~` lo microspheres should preferably be of a size between 0.5 and ~50~m, more preferably 10-lOO~Lm.
The microspheres can be made by procedures well known in the art including spray drying, coacervation and emulsification (see for example 5 Davis et al, Microsphere and Drug Therapy, Elsevier, 1984). For example, starch microspheres were prepared by an emulsion technique as follows:
5g potato starch were dissolved in 95ml of water at about 90C. A
second solution was prepared from 3g of polyethylene glycol (Mw =
10 6000) and 46ml of water. This solution was heated to about 70C, whereafter the warm starch solution was added while stirring, to form an emulsion. When the two-phase system had formed (with the starch solution as the inner phase) the mixture was allowed to cool to room te~ elal~lre under continued stirring, wherewith the inner phase was 15 converted to gel particles. The particles were filtered off at room te,ll~ rature and slurried in lOOml of ethanol, whereafter the particles were again filtered off and laid to dry in air.
The yield was 90%.
Soluble potato starch microspheres was prepared by a coacervation 20 technique as follows:
l5ml 5% starch solution (pH=7) was kept at a constant temperature of 70C and stirred (500rpm) while a 30% solution of polyethylene glycol was added (~7 ml) until phase separation had occurred, the system was stirred for further 15 min before it was cooled on ice during constant 25 stirring. The microspheres were then isolated by filtration and freeze-11 2~'30~'8~9'' dried. With a stirring speed of 500rpm particles with a mean size of33~m + ,um was produced.
The ion-exchange microspheres can be made from suitable ion-exchange matelial which already contains the al,pro~riate functional groups, or non-5 ion-exchange microspheres of suitable materials can then be function~ e~l by methods well known in the art to provide ion-exch~nge microspheres.
For the microsl)he,e compositions of the invention, a nicotine salt should ,rcf~,~bly be used to ensure that the nicotine is in its ionised form. The nicotine or nicotine salt is adsorbed to the microspheres by admixing with 10 the microspheres after their formation.
The microspheres, both ion-exchange and non-ion-exchange can be hardened by well known cross-linking procedures such as heat tre~tment or by using chemical cross-linking agents. Suitable agents include ~ ldehydes, including glyoxal, malonrli~ldehyde, succinicaldehyde, 15 adipaldehyde, glutaraldehyde and ph~h~l~ldehyde, diketones such as butadione, epichlorohydrin, polyphosphate and borate. Dialdehydes are used to cross-link proteins such as albumin by interaction with amino groups, and diketones form schiff bases with amino groups.
Epichlorohydrin activates compounds with nucleophiles such as amino or 20 hydroxyl to an epoxide derivative. The cross-linkers used for the ion-exchange microspheres should not be directed towards the relatively charged groups required for binding the nicotine.
The microsphere composition can be produced as a freeze-dried formulation and administration nasally by the usual methods, for example 25 by using a nasal insuMator. Such devices are well known.
WO 94127~;76 PCT/GB94101092 ~ 3~g~ ` ` 12 ~
As another alternative embodiment, the composition may comprise solely non-ion-exchange microspheres. In this case the nicotine or nicotine salt is incorporated into the microsphere during its formulation, and this incorporated nicotine will then be released from the microsphere gradually 5 to provide the controlled release effect. Excess nicotine is then mixed with the microspheres after their formulation and adsorbs to the microsphere as before. This nicotine will, as described above, be released from the microsphere immediately on contact with the nasal mucosa to provide the pulse effect.
10 Nicotine can be incorporated into a non-ion-exchange microsphere for ex~mrle as follows:
Human serum albumin based microspheres containing nicotine were prepared by an emulsification technique; 75.0ml of cotton seed oil was mixed with 25.0ml of petroleum ether and stirred for 10 min in a 200.0ml 15 beaker using a magnetic stirrer. Nicotine was dissolved in the HSA
solution (2, 3 or 5% w/v), to obtain drug solution (2%) in aqueous phase.
The aqueous phase containing HSA and nicotine was added to the ethereal solution of cotton seed oil dropwise with continuous stirring using a mech~nical stirrer at 1000 rpm for lS min. The microspheres were 20 stabilized by adding O.lml of 25% w/v glutaraldehyde solution with continuous stirring for 15 min or by adding the emulsion system to prehe~ted cotton seed oil (lOO.Oml) at 120C dropwise with continuous stirring. The microspheres were separated by centrifugation at 3000 x g for 15 min and washed with petroleum ether three times for complete 25 removal of oil adhering to the microsphere surface. The microspheres were filtered using Millipore filter and again washed with petroleum ether and ethanol. Preparation were freeze-dried and stored frozen until used in further studies. For 1 dose, using a 2, 3 or 5% w/v HSA solution, 30, 1~ 13 2l63~q 40 or 50mg of nicotine containing microspheres were mixed with for example, 2mg of nicotine or freeze dried in an aqueous solution cont~ining 2mg nicotine.
The composition of the invention may also be a liquid formulation 5 comprising a polymeric ion-exchange material. The polymeric material should provide a negatively charged group as discusserl above and also should provide a viscous solution to aid retention in the nasal cavity.
Preferably the material will gel when in contact with the nasal mucosa.
Suitable polymeric materials include gellan gum, welan, r~m~n, 10 ~lgin~te~ carboxymethylcellulose, sodium alginate, xanthan, agar, guar derivatives such as carboxymethyl guar gum, carageenan, dextran s~ h~te, keratan, dermatan, pectin. Polysaccharides and derivatives are particularly suitable ("Polysaccharides and derviatives" edited by R C
Whistler and J N BeMiller (3rd Ed.) Academic Press, San Diego 1993).
15 A ~r~ d material is gellan gum, which is the deacetylated form of the extracell~ r polysaccharide from Pseudomonas elodae. Native/high-acyl gellan is composed of a linear sequence of tetra-saccharide repe~ting units containing D-glucuronopyranosyl, D-glucopyranosyl and L-rhamnopyranosyl units and acyl groups.
20 Another preferred material is alginate. Alginate is composed of two building blocks of monomeric units namely ,~-D-mannuronopyranosyl and -guluronopyranosyl units. The ratio of D-mannuronic acid and L-guluronic acid components and their sequence predetermines the ~royel lies obsel~red for alginates extracted from different seaweed sources.
25 Welan is produced by an Alcaligenes species. Welan has the same basic ~1 633~,$! 1 re~e~ting unit as gellan but with a single glycosyl si~iech~in substituent.
The side unit can be either an ~-L-rhamnopyranosyl or an ~-L-mannopyranosyl unit linked (I 3) to the 4-0-substituted ,B-D-glucopyranosyl unit in the backbone.
S ~h~m~n is produced by an Alcaligenes species. ~h~m~n has the same repe~ting backbone unit as that of gellan but with a disaccharide side chain on 0-6 of the 3-0-substituted ,B-D-glucopyranosyl unit. The side chain is a f~-D-glucopyranosyl-(1-6)-cY-D-glucopyranosyl unit.
X~nth~n is produced by a number of Xanthomonas strains. The polymer 10 backbone, made up of (1~4)-linked ,~-D-glucopyranosyl units is identical to that of cellulose. To alternate D-glucosyl units at the 0-3 position, a tric~cch~ride side chain containing a D-glucoronosyl unit between two D-"anl1osyl units is ~tt~ched. The terminal ~-D-mannopyranosyl unit is glycosidically linked to the 0-4 position of the ,~-D-glucopyranosyluronic 15 acid unit, which in turn is glycosidically linked to the 0-2 position of an ~x-D-mannopyranosyl unit.
Carrageenan is a group of linear galactan polysaccharides extracted from red seaweeds of the Gigartinaceae, Hypneaceae, Solieriaceae, Phyllophoraceae and Furcellariaceae families that have an oster sulfate 20 content of 15-40% and contain alternatively (I ~3)-cY-D- and (1~4)-cY-D-glycosidic linkages.
Agar is a hydrophilic colloid extracted from certain marine algae of the class Rhodophyceae where it occurs as a structural carbohydrate in the cell walls (see also Kang and Pettitt: Xanthan, Gellan, Welan and Rhamsan in 25 Industrial gums by Whistler and BeMiller (Eds), Academic Press Inc.
London, 1993).
NASAL DRUG DELIVERY COMPOSITION CONTAINING NICOTINE ~
The present invention relates to compositions for nasal ~(lmini~tration and, more particularly, to compositions for nasal ~lmini~tration of nicotine.
5 Smoking remains the single most i",po.~ant preventable cause of death in modern society. It can be estimated that in the US alone more than 430 000 deaths in 1988 were attributable to cigarette smoking. At least nine out of ten smokers are to some extend depen~lerlt upon nicotine and 75% are moderately to strongly dependent and continue smoking 10 despite attempts to stop. In the United States the strong interest in stopping smoking is demonstrated by the fact that nearly 20 million peopLe try to quit smoking each year. Their need for ~ ition~l help can Ibe seen in the fact that more than 90% fail to m~int~in their ~hsti~lence.
15 The Imajor problem with nicotine is that it is highly addictive. Nicotine fulfils all criteria of an addictive drug, it is psychoactive, it affects the mood, it can act as a primary reinforcer, it induces tolerance, and physical as well as psychological changes occur on withdrawal.
Importantly, there is no direct evidence that nicotine itself is 20 carcinogenic or mutagenic, nor does it act as a tumour initiator, promoter or co-carcinogen. Similarly, none of the major metabolites of nicoline are known to be carcinogenic. In contrast, tobacco and especially tobacco smoke contains several potent carcinogens.
A mlajor limiting factor in the successful use of nicotine replacement 25 therapy for smoking cessation is the lack of an appro~,l,ate delivery WO 94/27~76 PCT/GB94/01092 ~ 6~g.a~ 2 system. When a person smokes a cigarette, the level of nicotine rise rapidly in the blood and in the brain with an interval of just 10-20 seconds between taking a puff and the nicotine arriving in the brain. The presently marketed nicotine replacement products, the transdermal nicotine patch 5 and the nicotine chewing gum, are not entirely s~ti~f~ctory in that they do not provide the patient with the nicotine "buzz" associated with smoking a cigarette, since they are both slowly acting controlled release systems where only low nicotine plasma levels are obtained. Hence clinical trails have shown that only about 20% - 30% of those smokers who have used 10 nicotine p~tches and nicotine chewing gum successfully quit smoking after one year compared to lS % of those smokers receiving behavioural support alone.
Transdermal patches seem to be no more effective than placebo in m~int~ining smoking cessation in the long term. The long term results lS after the use of patches alone have not been impressive Medical letter (Vol. 34, p37, 1992).
The nicotine chewing gum is a slow release preparation where the rate of release of nicotine will depend on the rate of chewing. It takes 20-30 min of vigorous chewing to release 95% of the nicotine content of the gum.
20 Without chewing or if the gum is accidently swallowed negligible amounts of nicotine are released. The gum contains 2 or 4 mg of nicotine. A
typical smoker needs about IS pieces of gum a day. The gum has an unpleasant taste and may be irritating to the mouth and throat. Potential side effects are heartburn and hiccups. Tired and aching jaws may be 25 experienced from intensive chewing and users rarely m~int~in blood nicotine concentrations above one third of their levels from smoking. The chewing gum is contraindicated in individuals with gastritis or active peptic ulcer di~e~ce and presents difficulties for those wearing dentures.
WO 94127576 PCTtGB94/01092 ~I630g~
US 3877468, US 3901248 and US 3845217 discloses a chewing gum comprising nicotine in the form of a complex with an insoluble cation-exchange base.
The nicotine patch placed on the skin will give a steady release of nicotine 5 over 24 hours and should be changed daily. The patch is available in three sizes delivery about 21, 14 and 7 mg/24 hours) With the patch in place it takes 3 - 4 hours to attain significant blood levels of nicotine. The continuous dosing provided by p~tches can disrupt the usual day/night variation in nicotine intake provided by smoking and can result in a total 10 dose of nicotine per 24 hour exceeding the normal smoking dose.
Moreover it seems that if nicotine is given both night and day con.l,ar~d to only daytime, sleep disturbances and nightmares can result. A potential side effect of the patch is skin irritation. A further disadvantage with the nicotine patch is that it is a passive system and for some individuals, a 15 closer involvement with the treatment is to be preferred.
Thus, neither the nicotine patch system nor the nicotine chewing gum system can be considered to be satisfactory for nicotine replacement thera~py and smoking cessation.
It is well established that nicotine is easily absorbed nasally. Nicotine 20 concentrations in the blood of regular users of dry snuff are similar to those of cigarette smokers and peak concentrations after a single pinch of snuff is reached in a time similar to that for smoking a cigarette. The absolute bioavailability of nicotine applied to different nasal regions has been measured by Johansson et al. (1991) in man. Single doses of 1 mg 25 were given and plasma concentrations followed over 6 hours.
Bioavailability, as compared to IV infusion was 60 to 7~%. The rate of absorption was fast. the maximum concentration being reached within WO 94/27!;76 PCT/GB94/01092 g~ 4 about 10 minutes. No differences could be found for different nasal treatments.
Nasal sprays containing nicotine have been suggested as an alternative approach for smoking cessation. The prior art has described various devices for the better delivery of nicotine. For example WO 8703813 a spray device with an electronic timer restricting doses to a predetermined number per session is described. A nasal aerosol spray supplying nicotine for anti-smoking therapy is mentioned as an advantage. In US 4655231 an improved snuff for nasal application of nicotine cont~ining a pure nicotine salt, a water soluble diluent and colouring and flavouring is described. The water soluble diluent is preferably an organic acid. The Ini~lulc allows rapid application of nicotine. GB 2133691 describes an aqueous solution of nicotine or a non-toxic salt of nicotine together with a non-irritating thickening agent. The composition has a pH of 2-6 and has a viscosity of at least 100 CP. The thirkçrling agent is a natural or synthetic polymer or an oil substance comprising the oil phase of an emulsion. A nicotine solution with a viscosity less than 100 CP has been mentioned in RD 239015. WO 9l/09599 discloses a smoking substitute for sublingual administration comprising a nicotine-cyclodextrin complex.
The composition is stated to have improved stability and taste, pH
independent release and reduced irritant sensation. It is also suggested that the composition could be given nasally.
The nasal nicotine systems discussed above were designed to give rapid absorption of nicotine, followed by a rapid decrease in the level of absorbed nicotine, mimicking the effect of smoking a cigarette. More recently, Sutherland et al. 1992, suggested that the rapid absorption of the nicotine when given nasally may be an important factor for smokers for whom other forms of replacements are too slow. Although nasal nicotine -- 21~3~
spray systems will provide the desired "buzz" effect, the benefit is short lived and will necessitate frequent dosing. This will be unacceptable to the potential user.
The pharmacokinetics of nicotine in man has been described in some detail 5 (for eY~ample see Benowitz 1990). The importance of including features associated with tolerance has been stressed. For example in the end of the day the response of the cigarette is blunted owing to the development of tolerance. Tolerance can develop and regress in cycles throughout the day. Rec~use of dose response and tolerance characteristics, habitual 10 smokers need to smoke at least lS cigarettes and consume 20-40 mg of nicotine per day to achieve the desired effect of cigarette smoking and to minimi~e withdrawal discomfort. The dose of systemically available nicotine absorbed by regular smokers averages about 1 mg per cigarette.
The daily nicotine intake of smokers averages about 25 mg. Two rninutes lS after the first cigarette the plasma nicotine level reaches about 13 ~g/l.
The nicotine peak plasma levels of regular smokers of lS or more cigarettes per day average about 35 ,ug/l during daytime.
We have now found that an improved nicotine replacement formulation can be achieved by providing a nasal composition which provides both an 20 initiall rapid release and absorption of nicotine, a pulse effect, followed by a controlled release and absorption of nicotine to provide a sustained high level of absorbed nicotine. The invention therefore provides a nasal drug delivery composition comprising nicotine or a pharmacologically acceptable salt or derivative thereof in which the nicotine or nicotine salt 25 or derivative is released as a pulse followed by a controlled release phase.
The pulse effect provides an initial rapid peak in plasma nicotine levels whiclh gives the "buzz" effect of smoking a cigarette. The controlled release phase then provides a more gradually increased and maintained ~G~ 6 high plasma level of nicotine, removing the craving for further nicotine, and avoiding the need to use the composition at frequent intervals.
The controlled release effect can be achieved by providing an ion-exchange material in the composition. By ion-exchange material we mean S a natural or synthetic material comprising ionisable groups and which have the ability to exchange ions attracted to their ionised groups with ions of the same charge present in solution. Nicotine is a basic drug and when ionised it carries a positive charge. The ion-exchange material must therefore be one which when ionised releases a positive ion leaving a 10 negative charge to which the ionised nicotine is attracted. The ion-excll~nge material forms a complex with the ionised nicotine and releases the nicotine slowly when in contact with the nasal mucosa.
The ion-exchange capacity of the ion-exchange material used should preferably be in the range 0.01-50 milli equivalents/g, more preferably 15 0.1-20 meq/g and most preferably 0.2-10 meq/g.
The ion-exchange material is preferably bio~(lhesive to aid its retention in the nasal cavity. By bioadhesive we mean a material which will adhere to the surface of the nasal cavity. The ion-exchange material gradually releases nicotine providing a controlled release and uptake of nicotine 20 across the nasal mucosa.
Natural or synthetic nicotine may be used or a pharmacologically-acceptable salt or derivative of nicotine. Nicotine forms water soluble salts and double salts with many metals and acids. The use of salt forms of nicotine avoids the problems associated with the free base form of 25 nicotine includes losses due to volatility and decomposition in the presence of oxygen. Preferred salts for use in the invention includes nicotine WO 94/27576 21 6 3 0 ~ ~ PCT/GB94/01092 dihydrogen tartrate, nicotine tartrate, nicotine hydrochloride, nicotine oxalaee, nicotine hydrogen tartrate, nicotine dihydrochloride, nicotine sulphate, 2-methyl nicotine and other nicotine derivatives. Nicotine dihydrogen tartrate or nicotine tartrate are especially preferred and also 2-5 methyl nicotine which has reduced side-effects on the heart. Unless otherwise stated, all amounts of nicotine stated are calcnl~t~d as the equivalent amount of nicotine free base.
The pulse release of nicotine may be achieved by providing a material which is not an ion-exchange material. The nicotine associated with this 10 mater;al will then be released immedi~tely on contact with the nasal mucosa for rapid absorption. Alternatively, excess nicotine is provided in the composition so that the ion-exchange material is overloaded with nicotine. The excess nicotine not bound by the ion-exchange material is available for immediate uptake on contact with the nasal mucosa. This 15 excess nicotine is also referred to throughout as "free nicotine".
Monovalent cations can also be included in the composition to compete with the nicotine for binding with the ion-exchange material, thus ensuring that some of the nicotine is left as free nicotine. Such cations should be non-toxic and pharmacologically acceptable, for example sodium, calcium 20 and ammonium.
The ion-exchange material may be in the form of bioadhesive microspheres, or may be an aqueous solution, suspension or freeze-dried preparation of a polymeric material.
It has previously been shown that bioadhesive microspheres are ab!e to 25 incre,ase the residence time of a formulation in the nasal cavity thereby increasing the time available for absorption of the drug (Illum et al, 1987).
a~ 8 It was also shown by Illum et al. (1988) that such a system was able to increase the absorption of the antibiotic agent, Gentamicin thereby allowing it to be given via the nasal route rather than by injection.
The use of the bioadhesive microspheres in drug delivery compositions for S transmucosal ~dministration has been described in WO 88/09163 and WO 89/03207.
The slow release of drugs and model compounds from ion-exch~nge microspheres has been the subject of previous work (Illum and Davis, 1982, US Patent 4847091). Here the strong binding of the drug to the 10 miclospheres via a process of ionic interaction has been used to modify drug release rates. The applications described were for pa~ e,~l ~ministration and the local administration of an anionic drug sodium cromoglycate to the nasal cavity. Various ion-exchange microsphere systems are described in the prior art (for example see Kown et al. (1990), 15 Cremers et al (1990) and Codde et al (1990)). None of these systems has been used nasally for nicotine administration.
The ion-exchange microspheres suitable for use in the present invention are microspheres which carry suitable anionic groups such as carboxylic acid resitlues, carboxymethyl groups, sulphopropyl groups and 20 methylsulphonate groups. Carboxylated starch microspheres are especially preferred. Other materials include hyaluronic acid, chondroitin slllrh~te, ~lgin~t5, heparin and heparin-albumin conjugates, as described in Kwon et al. (1991) albumin-poly (cY-L glutamic acid), albumin-poly (aspartic acid) or ion-exchange albumin microcapsules as described by Savaya et al 25 (1987). Ion-exchange resins (cation exchangers) can also be used such as Aminex-A-6 (Biorad)-a resin containing sulphonate groups or those with carboxymethyl or sulphopropyl groups. Cation exchanges which can be 9 2163-3~879 used include carboxymethyl dextran (CM SephadexlM) and sulphopropyl dextran (SP SephadexrM) carboxymethyl agarose (CM Sepharose~M), carboxymethyl cellulose, cellulose phosphate, sulphoxyethyl cellulose, agarose (Sepharose), cellulose beads (Sephacel) and dextran beads S (.Seph~dex) (all available from Pharmacia) are materials which such functional groups. Carboxylated starch microspheres (Cadexomer) are available from Perstorp.
Cation exchangers on polystyrene include the Amberlite and Dowex strongly acidic cation exchangers and the Amberlite weekly acidic cation 10 exchangers as described in the Sigma Chemical Co Ltd catalogue, 1993, plS91-1593. The Amberlite strongly acidic cation exch~n~ers have sulphonic acid functional groups and the weakly acidic ones have carboxylic acid functional groups. The Dowex exchanger has nl-clç~r sulphonic acid functional groups.
15 The ion-exchange microspheres can be used with free nicotine to provide both the fast pulse release of nicotine and the controlled release, or can be mixed with non-ion-exchange microsphere. Nicotine is adsorbed to the surface of the non-ion-exchange microsphere and will be released quickly on contact with the nasal mucosa to provide the pulsed effect. Suitable 20 materlals for use as non-ion-exchange microspheres include starch, gelatine, collagen and albumin. When a mixture of ion exchange and non-ion-exchange microspheres are used, the composition should contain between 50:1 and 1:1 of ion-exchange to non-ion-exchange microspheres, preferably 25:1 to 5:1 and more preferably 10:1.
25 The term microsphere as used herein is defined as substantially spherical particles which can be a monolithic solid sphere or in the form of a small capsule. To ensure correct deposition in the nasal cavity, the 3Q8~` lo microspheres should preferably be of a size between 0.5 and ~50~m, more preferably 10-lOO~Lm.
The microspheres can be made by procedures well known in the art including spray drying, coacervation and emulsification (see for example 5 Davis et al, Microsphere and Drug Therapy, Elsevier, 1984). For example, starch microspheres were prepared by an emulsion technique as follows:
5g potato starch were dissolved in 95ml of water at about 90C. A
second solution was prepared from 3g of polyethylene glycol (Mw =
10 6000) and 46ml of water. This solution was heated to about 70C, whereafter the warm starch solution was added while stirring, to form an emulsion. When the two-phase system had formed (with the starch solution as the inner phase) the mixture was allowed to cool to room te~ elal~lre under continued stirring, wherewith the inner phase was 15 converted to gel particles. The particles were filtered off at room te,ll~ rature and slurried in lOOml of ethanol, whereafter the particles were again filtered off and laid to dry in air.
The yield was 90%.
Soluble potato starch microspheres was prepared by a coacervation 20 technique as follows:
l5ml 5% starch solution (pH=7) was kept at a constant temperature of 70C and stirred (500rpm) while a 30% solution of polyethylene glycol was added (~7 ml) until phase separation had occurred, the system was stirred for further 15 min before it was cooled on ice during constant 25 stirring. The microspheres were then isolated by filtration and freeze-11 2~'30~'8~9'' dried. With a stirring speed of 500rpm particles with a mean size of33~m + ,um was produced.
The ion-exchange microspheres can be made from suitable ion-exchange matelial which already contains the al,pro~riate functional groups, or non-5 ion-exchange microspheres of suitable materials can then be function~ e~l by methods well known in the art to provide ion-exch~nge microspheres.
For the microsl)he,e compositions of the invention, a nicotine salt should ,rcf~,~bly be used to ensure that the nicotine is in its ionised form. The nicotine or nicotine salt is adsorbed to the microspheres by admixing with 10 the microspheres after their formation.
The microspheres, both ion-exchange and non-ion-exchange can be hardened by well known cross-linking procedures such as heat tre~tment or by using chemical cross-linking agents. Suitable agents include ~ ldehydes, including glyoxal, malonrli~ldehyde, succinicaldehyde, 15 adipaldehyde, glutaraldehyde and ph~h~l~ldehyde, diketones such as butadione, epichlorohydrin, polyphosphate and borate. Dialdehydes are used to cross-link proteins such as albumin by interaction with amino groups, and diketones form schiff bases with amino groups.
Epichlorohydrin activates compounds with nucleophiles such as amino or 20 hydroxyl to an epoxide derivative. The cross-linkers used for the ion-exchange microspheres should not be directed towards the relatively charged groups required for binding the nicotine.
The microsphere composition can be produced as a freeze-dried formulation and administration nasally by the usual methods, for example 25 by using a nasal insuMator. Such devices are well known.
WO 94127~;76 PCT/GB94101092 ~ 3~g~ ` ` 12 ~
As another alternative embodiment, the composition may comprise solely non-ion-exchange microspheres. In this case the nicotine or nicotine salt is incorporated into the microsphere during its formulation, and this incorporated nicotine will then be released from the microsphere gradually 5 to provide the controlled release effect. Excess nicotine is then mixed with the microspheres after their formulation and adsorbs to the microsphere as before. This nicotine will, as described above, be released from the microsphere immediately on contact with the nasal mucosa to provide the pulse effect.
10 Nicotine can be incorporated into a non-ion-exchange microsphere for ex~mrle as follows:
Human serum albumin based microspheres containing nicotine were prepared by an emulsification technique; 75.0ml of cotton seed oil was mixed with 25.0ml of petroleum ether and stirred for 10 min in a 200.0ml 15 beaker using a magnetic stirrer. Nicotine was dissolved in the HSA
solution (2, 3 or 5% w/v), to obtain drug solution (2%) in aqueous phase.
The aqueous phase containing HSA and nicotine was added to the ethereal solution of cotton seed oil dropwise with continuous stirring using a mech~nical stirrer at 1000 rpm for lS min. The microspheres were 20 stabilized by adding O.lml of 25% w/v glutaraldehyde solution with continuous stirring for 15 min or by adding the emulsion system to prehe~ted cotton seed oil (lOO.Oml) at 120C dropwise with continuous stirring. The microspheres were separated by centrifugation at 3000 x g for 15 min and washed with petroleum ether three times for complete 25 removal of oil adhering to the microsphere surface. The microspheres were filtered using Millipore filter and again washed with petroleum ether and ethanol. Preparation were freeze-dried and stored frozen until used in further studies. For 1 dose, using a 2, 3 or 5% w/v HSA solution, 30, 1~ 13 2l63~q 40 or 50mg of nicotine containing microspheres were mixed with for example, 2mg of nicotine or freeze dried in an aqueous solution cont~ining 2mg nicotine.
The composition of the invention may also be a liquid formulation 5 comprising a polymeric ion-exchange material. The polymeric material should provide a negatively charged group as discusserl above and also should provide a viscous solution to aid retention in the nasal cavity.
Preferably the material will gel when in contact with the nasal mucosa.
Suitable polymeric materials include gellan gum, welan, r~m~n, 10 ~lgin~te~ carboxymethylcellulose, sodium alginate, xanthan, agar, guar derivatives such as carboxymethyl guar gum, carageenan, dextran s~ h~te, keratan, dermatan, pectin. Polysaccharides and derivatives are particularly suitable ("Polysaccharides and derviatives" edited by R C
Whistler and J N BeMiller (3rd Ed.) Academic Press, San Diego 1993).
15 A ~r~ d material is gellan gum, which is the deacetylated form of the extracell~ r polysaccharide from Pseudomonas elodae. Native/high-acyl gellan is composed of a linear sequence of tetra-saccharide repe~ting units containing D-glucuronopyranosyl, D-glucopyranosyl and L-rhamnopyranosyl units and acyl groups.
20 Another preferred material is alginate. Alginate is composed of two building blocks of monomeric units namely ,~-D-mannuronopyranosyl and -guluronopyranosyl units. The ratio of D-mannuronic acid and L-guluronic acid components and their sequence predetermines the ~royel lies obsel~red for alginates extracted from different seaweed sources.
25 Welan is produced by an Alcaligenes species. Welan has the same basic ~1 633~,$! 1 re~e~ting unit as gellan but with a single glycosyl si~iech~in substituent.
The side unit can be either an ~-L-rhamnopyranosyl or an ~-L-mannopyranosyl unit linked (I 3) to the 4-0-substituted ,B-D-glucopyranosyl unit in the backbone.
S ~h~m~n is produced by an Alcaligenes species. ~h~m~n has the same repe~ting backbone unit as that of gellan but with a disaccharide side chain on 0-6 of the 3-0-substituted ,B-D-glucopyranosyl unit. The side chain is a f~-D-glucopyranosyl-(1-6)-cY-D-glucopyranosyl unit.
X~nth~n is produced by a number of Xanthomonas strains. The polymer 10 backbone, made up of (1~4)-linked ,~-D-glucopyranosyl units is identical to that of cellulose. To alternate D-glucosyl units at the 0-3 position, a tric~cch~ride side chain containing a D-glucoronosyl unit between two D-"anl1osyl units is ~tt~ched. The terminal ~-D-mannopyranosyl unit is glycosidically linked to the 0-4 position of the ,~-D-glucopyranosyluronic 15 acid unit, which in turn is glycosidically linked to the 0-2 position of an ~x-D-mannopyranosyl unit.
Carrageenan is a group of linear galactan polysaccharides extracted from red seaweeds of the Gigartinaceae, Hypneaceae, Solieriaceae, Phyllophoraceae and Furcellariaceae families that have an oster sulfate 20 content of 15-40% and contain alternatively (I ~3)-cY-D- and (1~4)-cY-D-glycosidic linkages.
Agar is a hydrophilic colloid extracted from certain marine algae of the class Rhodophyceae where it occurs as a structural carbohydrate in the cell walls (see also Kang and Pettitt: Xanthan, Gellan, Welan and Rhamsan in 25 Industrial gums by Whistler and BeMiller (Eds), Academic Press Inc.
London, 1993).
2 1 6 ~ O ~ 9 Mixtures of gellan with other polymers such as alginate can be used, gelling of the mixture being caused by the gellan gum. Other combinations of gums can also be used, particularly where the combination gives a synergistic effect, for example in terms of gelation 5 properties. An example is xanthan - locust bean gum combinations.
The advantage of gellan over other materials is that it can be ~lmini~tered as a lFluid system but in the nasal cavity the system will gel, thereby providing a bio~dhesive effect and holding the drug at the absorptive surface for an extended period of time.
10 The grade of gellan gum can be Gelrite or Kelcogel from Kelco Int, Ltd.
or other similar grades from other manufacturers. The gellan can be prepared at a concentration of 0.1 w/v to 15~ but a preferred range of col,cenllations is 0.2% to 1%.
For gelling to occur, particularly of gellan gum, monovalent or divalent 15 cations must be ~rese"L in the composition.
Suitable cations include sodium, potassium, magnesium and calcium. The ionic concentration is chosen according to the degree of gelling required, and allowing for the effect that the ionised drug present may have on gelling. At a 0.2% gum concentration, the divalent ions, calcium and 20 m~gnesium give maximum gel hardness and modulus at molar concentrations approximately one fortieth ( 1/40) of those required with the monovalent ions, sodium and potassium. A finite concer.tldtion of each cation is required to induce gelation. For the nasal formulations of the invention the ionic strength is kept sufficiently low to obtain a low 25 viscosity formulation but sufficiently high to ensure gelation once administration into the nasal cavity where gelation will take place due to 2i~3~ 16 ~
the presence of cations int he nasal liquid. The ionic strength for a 0.5 %
gellan gum can be in the range of 0.1 mM - SOmM for monovalent cations with the preferred range being lmM - SmM and O.lmM - SmM for divalent cations with the preferred range being O.lSmM - lmM. For S higher concentrations of gellan gum the ionic strengths should be lowered accordingly. The cations will complete with the positively charged nicotine for binding with the polymeric material, and whilst this may be desirable to a certain degree to ensure the presence of free nicotine in the composition, the concentration of cations should be controlled so that sufficient nicotine will bind with the ion-exchange polymeric material.
The complex between nicotine and the ion-exchange material forms as a result of ionic interaction between the negatively charged polymeric material and the positively charged nicotine. The pH of the co-,-posilion must therefore be such that the two species are fully ionised. The pH
lS should be kept in the range pH 3 to 8, preferably pH 4 to 6, by the presence of a~ro~-iate buffers or acids. For these ion-exchange materials the nicotine can be added either as nicotine itself or as a nicotine salt or derivative as the control of the pH by the addition of ay~ro~Jl;ate acids will ensure that the nicotine is in its ionised form.
The liquid formulations are administered using well-known nasal spray devices. If the formulations are freeze-dried, they can be ~lministpred using a nasal insufflator, as for the microsphere preparations.
In a liquid formulation, the polymeric ion-exchange material will typically be provided in a concentration of from 0.01% to 20%, preferably O.OS-10%, more preferably 0.1% - 5%.
The compositions of the invention can also contain any other WO 94/27576 21~ 0 ~ PCT/GB94101092 pharmacologically-acceptable, non-toxic ingredients such as preservatives, antioxidants, flavourings etc. Benzalkonium chloride may be used as a preservative. However, as this is positively charged, it will complete with the ionised nicotine for binding with the ion-exchange material and can - 5 thel~fole be used to regulate the nicotine binding and ensure the presence of free nicotine for the pulse absorption.
The nicotine or nicotine salt or derivative should be present in an amount to provide a ratio of between 50:1 to 1:1, preferably 25:1 to 2:1, most preferably 15:1 to 5:1 of nicotine bound to the ion-exchange material and 10 free nicotine or nicotine bound to the non-ion exchange material c~lcl~l~t~
as the equivalent nicotine free base. The amount of nicotine or salt or derivative used will be chosen according to the dose required, but the col"~osi~ion will typically deliver an initial pulse of 0.2 to 3mg, ~lefcldl)ly lmg, equivalent nicotine free base for rapid absorption and 5-20mg, 15 preferably lOmg equivalent nicotine free base rele~cecl in a controlled manner for sustained absorption. The composition should preferably deliver the pulse of nicotine for absorption over a period of 30 minutes, preferably 20 minutes and more preferably 10 or S minutes after administration. The composition should preferably deliver controlled 20 release of nicotine for absorption over a period of 12 hours, preferably 10 hours and more preferably 6 hours following administration. For a liquid formulation the concentration of nicotine in the formulation, calc~ t~cl as the equivalent free base would be 1-20%, preferably 1-10%, more p~cfclably 2-7%. For a freeze-dried powder or microsphere yl~al~tion~
the concentration would be 1-75%, preferably 2-50%, more preferably 5-25%. The formulations would typically be administered every six hours.
However the composition will provide for more extended periods between administration, say 10 hours, for night thlle use.
The advantage of gellan over other materials is that it can be ~lmini~tered as a lFluid system but in the nasal cavity the system will gel, thereby providing a bio~dhesive effect and holding the drug at the absorptive surface for an extended period of time.
10 The grade of gellan gum can be Gelrite or Kelcogel from Kelco Int, Ltd.
or other similar grades from other manufacturers. The gellan can be prepared at a concentration of 0.1 w/v to 15~ but a preferred range of col,cenllations is 0.2% to 1%.
For gelling to occur, particularly of gellan gum, monovalent or divalent 15 cations must be ~rese"L in the composition.
Suitable cations include sodium, potassium, magnesium and calcium. The ionic concentration is chosen according to the degree of gelling required, and allowing for the effect that the ionised drug present may have on gelling. At a 0.2% gum concentration, the divalent ions, calcium and 20 m~gnesium give maximum gel hardness and modulus at molar concentrations approximately one fortieth ( 1/40) of those required with the monovalent ions, sodium and potassium. A finite concer.tldtion of each cation is required to induce gelation. For the nasal formulations of the invention the ionic strength is kept sufficiently low to obtain a low 25 viscosity formulation but sufficiently high to ensure gelation once administration into the nasal cavity where gelation will take place due to 2i~3~ 16 ~
the presence of cations int he nasal liquid. The ionic strength for a 0.5 %
gellan gum can be in the range of 0.1 mM - SOmM for monovalent cations with the preferred range being lmM - SmM and O.lmM - SmM for divalent cations with the preferred range being O.lSmM - lmM. For S higher concentrations of gellan gum the ionic strengths should be lowered accordingly. The cations will complete with the positively charged nicotine for binding with the polymeric material, and whilst this may be desirable to a certain degree to ensure the presence of free nicotine in the composition, the concentration of cations should be controlled so that sufficient nicotine will bind with the ion-exchange polymeric material.
The complex between nicotine and the ion-exchange material forms as a result of ionic interaction between the negatively charged polymeric material and the positively charged nicotine. The pH of the co-,-posilion must therefore be such that the two species are fully ionised. The pH
lS should be kept in the range pH 3 to 8, preferably pH 4 to 6, by the presence of a~ro~-iate buffers or acids. For these ion-exchange materials the nicotine can be added either as nicotine itself or as a nicotine salt or derivative as the control of the pH by the addition of ay~ro~Jl;ate acids will ensure that the nicotine is in its ionised form.
The liquid formulations are administered using well-known nasal spray devices. If the formulations are freeze-dried, they can be ~lministpred using a nasal insufflator, as for the microsphere preparations.
In a liquid formulation, the polymeric ion-exchange material will typically be provided in a concentration of from 0.01% to 20%, preferably O.OS-10%, more preferably 0.1% - 5%.
The compositions of the invention can also contain any other WO 94/27576 21~ 0 ~ PCT/GB94101092 pharmacologically-acceptable, non-toxic ingredients such as preservatives, antioxidants, flavourings etc. Benzalkonium chloride may be used as a preservative. However, as this is positively charged, it will complete with the ionised nicotine for binding with the ion-exchange material and can - 5 thel~fole be used to regulate the nicotine binding and ensure the presence of free nicotine for the pulse absorption.
The nicotine or nicotine salt or derivative should be present in an amount to provide a ratio of between 50:1 to 1:1, preferably 25:1 to 2:1, most preferably 15:1 to 5:1 of nicotine bound to the ion-exchange material and 10 free nicotine or nicotine bound to the non-ion exchange material c~lcl~l~t~
as the equivalent nicotine free base. The amount of nicotine or salt or derivative used will be chosen according to the dose required, but the col"~osi~ion will typically deliver an initial pulse of 0.2 to 3mg, ~lefcldl)ly lmg, equivalent nicotine free base for rapid absorption and 5-20mg, 15 preferably lOmg equivalent nicotine free base rele~cecl in a controlled manner for sustained absorption. The composition should preferably deliver the pulse of nicotine for absorption over a period of 30 minutes, preferably 20 minutes and more preferably 10 or S minutes after administration. The composition should preferably deliver controlled 20 release of nicotine for absorption over a period of 12 hours, preferably 10 hours and more preferably 6 hours following administration. For a liquid formulation the concentration of nicotine in the formulation, calc~ t~cl as the equivalent free base would be 1-20%, preferably 1-10%, more p~cfclably 2-7%. For a freeze-dried powder or microsphere yl~al~tion~
the concentration would be 1-75%, preferably 2-50%, more preferably 5-25%. The formulations would typically be administered every six hours.
However the composition will provide for more extended periods between administration, say 10 hours, for night thlle use.
3~g~ ~
Specific embodiments of the invention will now be described in the following examples and with reference to the Figures in which:
Figure 1 is a computer generated curve of the time course of nicotine concenl,~tion in the body compartment of the model system 5 following intranasal administration of a composition according to the invention, containing lOOO~g nicotine for immediate release and 10000~g for controlled release, compared to that of a single immediate release dose of lOOO~g alone;
Figure 2 is a Franz diffusion cell; and Figure 3 is a closed loop system containing a Franz diffusion cell.
In the present invention it has been found that an improved nicotine replacement therapy can be achieved by a nasal nicotine composition which provides a two phase release and absorption of nicotine - an initial rapid pulse of nicotine followed by a controlled release phase.
15 Computer modelling studies have shown the pattern of nicotine levels that will be achieved with such a system and this is shown in Figure 1. From this it will be seen that the composition of the invention provides a nicotine profile which shows an initial sharp peak of nicotine absorption followed by a larger but more gradual and sustained peak. This is in 20 contrast to the sharp but rapidly decreasing peak found with a single immediate release dose of nicotine achieved for example with the currently known nasal nicotine delivery systems or seen when smoking a cigarette.
Specific embodiments of the invention are shown in the following examples.
wo 94/27576 PcT/Gss4/o1os2 Example 1 Starclh microspheres (Eldexomer) and starch microspheres that carried carboxyl groups (Cadexomer) were obtained from Perstorp Fine 5 Chemical Companies, Sweden. The microspheres had a particle size in the range of 53-106 micron diameter in the unswollen state. The microspheres (Sg) at a ratio of 10:1 carboxylated to non-carboxylated were mixed with 20ml of an aqueous solution of nicotine (pH adjusted to 7) at a concentration of 5%. The system was freeze dried and doses 10 of 50mg powder were packed into gelatin capsules for ~drnini~tration by a nasal insufflator device. The immediate release component was lmg and the controlled release component 9mg.
Example 2 An aqueous solution was prepared containing 25mg/ml of sodium 15 ~I~in~te and 2mg/ml gellan gum using heating to 70C and continuous stirring. Nicotine dihydrogen tartrate to give a final concentration of 75mg/ml was added. The system was mixed for 6 hours to allow interaction between the gellan and the nicotine.
Exannple 3 20 A nicotine-alginate complex that can provide controlled release of nicotine in the nasal cavity can be prepared by mixing a solution of sodium alginate and nicotine dihydrogen tartrate. The concentrations of the alginate and nicotine are chosen to provide a 1:1 stoichiometric complex. The complex together with a suitable dose of free nicotine 25 salt that will provide the pulse release phase can be administered nasally as a viscous solution or can be dried (for example by standard WO 94/27576 C? 1 (~) 308 ~ PCT/GB94/01092 procedures of freeze or spray drying) and administered as a powder or a suspension. Such powder complex can be administered as the material itself or in combination with bioadhesive microspheres and powders as described by Illum et al. 1987, 1988.
5 4.6g of nicotine dihydrogen tartrate (Sigma) was dispersed in 100ml of ~istille.d water containing 1.75g of sodium alginate (low molec~ r weight grade - Protan Laboratories) by stirring over a period of 24 hours. The nicotine - alginate complex was recovered by a process of freeze drying.
Other grades of alginate can also be used.
10 Example 4 An aqueous solution was prepared containing 20mg/ml of sodium alginate and 51mg/ml of nicotine dihydrogen tartrate. This concentration of nicotine salt was equivalent to 18mg/ml of nicotine base.
The release of nicotine from this formulations was measured using a Franz 15 diffusion cell apparatus (see Figure 2). The Franz diffusion cell as shown in Figure 2 comprises:
1 - sample compartment 2 - metal clasp to secure membrane 3 - flange cap 4 - membrane 5 - water jacket 6 - feed from water bath 7 - exit to water bath 8 - stirrer WO 94127576 ~CT/GB94/01092 q ~! 21 9 - eluant outlet (to cuvette) 10 - eluant inlet from peristaltic pump The system in Figure 3 comprises:
Specific embodiments of the invention will now be described in the following examples and with reference to the Figures in which:
Figure 1 is a computer generated curve of the time course of nicotine concenl,~tion in the body compartment of the model system 5 following intranasal administration of a composition according to the invention, containing lOOO~g nicotine for immediate release and 10000~g for controlled release, compared to that of a single immediate release dose of lOOO~g alone;
Figure 2 is a Franz diffusion cell; and Figure 3 is a closed loop system containing a Franz diffusion cell.
In the present invention it has been found that an improved nicotine replacement therapy can be achieved by a nasal nicotine composition which provides a two phase release and absorption of nicotine - an initial rapid pulse of nicotine followed by a controlled release phase.
15 Computer modelling studies have shown the pattern of nicotine levels that will be achieved with such a system and this is shown in Figure 1. From this it will be seen that the composition of the invention provides a nicotine profile which shows an initial sharp peak of nicotine absorption followed by a larger but more gradual and sustained peak. This is in 20 contrast to the sharp but rapidly decreasing peak found with a single immediate release dose of nicotine achieved for example with the currently known nasal nicotine delivery systems or seen when smoking a cigarette.
Specific embodiments of the invention are shown in the following examples.
wo 94/27576 PcT/Gss4/o1os2 Example 1 Starclh microspheres (Eldexomer) and starch microspheres that carried carboxyl groups (Cadexomer) were obtained from Perstorp Fine 5 Chemical Companies, Sweden. The microspheres had a particle size in the range of 53-106 micron diameter in the unswollen state. The microspheres (Sg) at a ratio of 10:1 carboxylated to non-carboxylated were mixed with 20ml of an aqueous solution of nicotine (pH adjusted to 7) at a concentration of 5%. The system was freeze dried and doses 10 of 50mg powder were packed into gelatin capsules for ~drnini~tration by a nasal insufflator device. The immediate release component was lmg and the controlled release component 9mg.
Example 2 An aqueous solution was prepared containing 25mg/ml of sodium 15 ~I~in~te and 2mg/ml gellan gum using heating to 70C and continuous stirring. Nicotine dihydrogen tartrate to give a final concentration of 75mg/ml was added. The system was mixed for 6 hours to allow interaction between the gellan and the nicotine.
Exannple 3 20 A nicotine-alginate complex that can provide controlled release of nicotine in the nasal cavity can be prepared by mixing a solution of sodium alginate and nicotine dihydrogen tartrate. The concentrations of the alginate and nicotine are chosen to provide a 1:1 stoichiometric complex. The complex together with a suitable dose of free nicotine 25 salt that will provide the pulse release phase can be administered nasally as a viscous solution or can be dried (for example by standard WO 94/27576 C? 1 (~) 308 ~ PCT/GB94/01092 procedures of freeze or spray drying) and administered as a powder or a suspension. Such powder complex can be administered as the material itself or in combination with bioadhesive microspheres and powders as described by Illum et al. 1987, 1988.
5 4.6g of nicotine dihydrogen tartrate (Sigma) was dispersed in 100ml of ~istille.d water containing 1.75g of sodium alginate (low molec~ r weight grade - Protan Laboratories) by stirring over a period of 24 hours. The nicotine - alginate complex was recovered by a process of freeze drying.
Other grades of alginate can also be used.
10 Example 4 An aqueous solution was prepared containing 20mg/ml of sodium alginate and 51mg/ml of nicotine dihydrogen tartrate. This concentration of nicotine salt was equivalent to 18mg/ml of nicotine base.
The release of nicotine from this formulations was measured using a Franz 15 diffusion cell apparatus (see Figure 2). The Franz diffusion cell as shown in Figure 2 comprises:
1 - sample compartment 2 - metal clasp to secure membrane 3 - flange cap 4 - membrane 5 - water jacket 6 - feed from water bath 7 - exit to water bath 8 - stirrer WO 94127576 ~CT/GB94/01092 q ~! 21 9 - eluant outlet (to cuvette) 10 - eluant inlet from peristaltic pump The system in Figure 3 comprises:
11 - sample inlet 12 - Franz cell 13 - flow through cuvette 14 - UV spectrophotometer 15 - printer 16 - peristaltic pump 10 Twenty microlitres of formulation (equivalent to 0.36 mg of nicotine) were applied to the membrane in the sample compartment (0.45 ~m cellu~ose nitrate membrane). Drug diffused across the membrane into the diffusion cell which contained a sthllulated nasal electrolyte solution (150mEq/1 Na+, 40 mEq/l K+, 8 mEq/l Ca~+). The solution was 15 continuously circulated through a flow cell and the appearance of nicotine monitored spectrophotometrically.
The release characteristics of the formulation indicated a biphasic profile demonstrating initial pulse release followed by a sustained release phase.
Example 5 20 Into a lOml glass vial was weighed SOmg of Amberlite IR 120 ion-exchange resin (Rohm & Haas, Philadelphia). The resin was suspended in 3.33ml of an aqueous solution containing a total of 15.4 mg of nicotine dihydrogen tartrate (equivalent to Smg of nicotine base). The mixture was frozen in liquid nitrogen and Iyophilised and mixed with 2mg of (free) 0g 22 nicotine dihydrogen tartrate.
Example 6 Into a 10ml glass vial was weighed 50mg of Amberlite IR 120 ion-exchange resin (Rohm & Haas, Philadelphia). The resin was suspended 5 in 3.33ml of an aqueous solution containing a total of 30.8mg of nicotine dihydrogen tartrate (equivalent to 10mg of nicotine base). The mixture was frozen in liquid nitrogen and Iyophilised.
I~xample 7 A solution of gellan at a concentration of 0.2% w1w was prepared by l0 dispersing 20mg gellan gum in 10ml of distilled water and heating to 70C
during continuous stirring until the gellan gum was dissolved. Nicotine tartrate to give a final concentration of 3 .5 % was added. The system was mixed for 6 hQurs to allow interaction between the gellan and the nicotine.
F.xample 8 I5 It is possible to prepare combinations of microsphere materials. Into a l0ml glass vial were weighed 50mg of Eldexomer starch (non-carboxylated) microspheres (Perstorp, Sweden). These are non-ion-exch~nge microspheres. The microspheres were suspended in 3.33ml of an aqueous solution containing a total of 15.4mg of nicotine dihydrogen 20 tartrate (equivalent to Smg of nicotine base). The mixture was frozen in liquid nitrogen and Iyophilised.
The release characteristics of the lyophilised formulation were measured using the Franz diffilsion cell. A rapid release profile was found. One WO 94/27~76 PCT/GB94/01092 23 ~(~1'30~)9 part of the Eldexomer microsphere nicotine preparation was mixed with an equal proportion of the microsphere preparation described in F~mrle 5. Tlle release demonstrated a pulse release of nicotine followed by a slower release phase. In this manner by mixing microspheres of different S ~ro~e~,lies it is possible to obtain different release profiles for int~-nde-l use lll VlVO.
Resi~ies using in smoking cessation or as a nicotine replacement, the novel nasal ,delivery systems for nicotine herein described could also be useful when it is required to dose nicotine for therapeutic reasons. These include 10 its use as a cognitive enhancer in ulcerative colitis, weight reduction, Parkinsons di~e~e, Alzheimers dise~e, narcolepsy, de~ ssion, sleep a~)noea.
References Benowitz, N.L., Pharmacological aspects of cigarette smoking and nicotine addition. N. Engl. J. Med., 319, 1318 (1988).
Benowitz, N.L., Pharmacokinetic consideration in understanding nicotine dependence, in The Biology of Nicotine Dependence, P 186, Ciba Foundation Symposillm, 152, Wiley Chichester, 1990.
Henningfield, J.E. and Stilzer, M.L (Editors) new Developments in 20 Nicotiine Delivery Systems, Cortlandt Communications, New York 1991.
Illum9 L., Farraj, N.F., Critchley, H and Davis S.S., Nasal administration of gentamicin using a novel microsphere delivery system, Int. J. Pharm, 46 261 (1988).
~ 3~ 24 Illum, L., J0rgensen, H., Bisgaard, H., Krogsgaard, O. and Rossing, N., Bioadhesive microspheres as a potential nasal drug delivery system, Int.
J. Pharm, 39, 189 (1987).
Illum, L., and Davis, S.S., Cellulose micropsheres as a sustained release system for parc,.ler~l administration, Int. J. Pharm, 11, 323 (1982).
Johansson, C.J., Olsson, P., Bende, M., Carlsson, T. and Gunnarsson, P.O., Absolute bioavailability of nicotine applied to different nasal regions, Eur. J. Clin. Pharmacol., 41, 585 (1991).
Russell, M.A.H., Jarvis, M.J., Feyerabend, C and Ferno. O., Nasal 10 nicotine solution, a potential aid to giving up smoking, Br. Med. J. 286, 683 (1983).
Sutherland, G., Stapleton, J.A., Russell, M.A.H., Jarvis, M.J., Hajek, P., Rdc~ er, M., and Feyerabend, C., Randomised controlled trial of nasal nicotine spray in smoking cessation, Lancet, 340, 324 (1992).
15 Codde, J.P., Burton, M.A., Kelleher, D.K., Archer, S.G., and Gray, B.N., Reduced Toxicity of Adriamycin by incorporation into ion-exchange micropheres. A therapeutic study using a rat liver. Anti cancer Res. 10 1715-1718 (1990).
Kwon, G.S., Bae, Y.H., Kim, S.W., Cremers, H and Feijen, J., 20 Preparation and characterisation of microspheres of albumin-heparin conjugates. J. Colloid Interface Sci. 143, 501 (1991).
Sawaya, A., Benoit, J.P., and Benita, S., Binding mechanism of Doxorubicin in ion-exchange albumin microspheres. J. Pharm. Sci. 76 475 25 ~16~0~9 (1987).
Kwon, G.S., Bae, Y.H., Cremers, H., Feijen, J., Kim, S.W., Release of macromolecules from albumin-heparin microspheres, Int. J. Pharm., 79, 191 (1992).
S Cremers, H.P.M., Feijen, J., Kwon, G., Bae, Y.H., Kim, S.W., Noteborn, H.P.J.M., McVie, J.G., Albumin-Heparin Micropheres as CalT,iers for Cytostatic Agents, J. Controlled Rel., 11, 167 (1990).
The release characteristics of the formulation indicated a biphasic profile demonstrating initial pulse release followed by a sustained release phase.
Example 5 20 Into a lOml glass vial was weighed SOmg of Amberlite IR 120 ion-exchange resin (Rohm & Haas, Philadelphia). The resin was suspended in 3.33ml of an aqueous solution containing a total of 15.4 mg of nicotine dihydrogen tartrate (equivalent to Smg of nicotine base). The mixture was frozen in liquid nitrogen and Iyophilised and mixed with 2mg of (free) 0g 22 nicotine dihydrogen tartrate.
Example 6 Into a 10ml glass vial was weighed 50mg of Amberlite IR 120 ion-exchange resin (Rohm & Haas, Philadelphia). The resin was suspended 5 in 3.33ml of an aqueous solution containing a total of 30.8mg of nicotine dihydrogen tartrate (equivalent to 10mg of nicotine base). The mixture was frozen in liquid nitrogen and Iyophilised.
I~xample 7 A solution of gellan at a concentration of 0.2% w1w was prepared by l0 dispersing 20mg gellan gum in 10ml of distilled water and heating to 70C
during continuous stirring until the gellan gum was dissolved. Nicotine tartrate to give a final concentration of 3 .5 % was added. The system was mixed for 6 hQurs to allow interaction between the gellan and the nicotine.
F.xample 8 I5 It is possible to prepare combinations of microsphere materials. Into a l0ml glass vial were weighed 50mg of Eldexomer starch (non-carboxylated) microspheres (Perstorp, Sweden). These are non-ion-exch~nge microspheres. The microspheres were suspended in 3.33ml of an aqueous solution containing a total of 15.4mg of nicotine dihydrogen 20 tartrate (equivalent to Smg of nicotine base). The mixture was frozen in liquid nitrogen and Iyophilised.
The release characteristics of the lyophilised formulation were measured using the Franz diffilsion cell. A rapid release profile was found. One WO 94/27~76 PCT/GB94/01092 23 ~(~1'30~)9 part of the Eldexomer microsphere nicotine preparation was mixed with an equal proportion of the microsphere preparation described in F~mrle 5. Tlle release demonstrated a pulse release of nicotine followed by a slower release phase. In this manner by mixing microspheres of different S ~ro~e~,lies it is possible to obtain different release profiles for int~-nde-l use lll VlVO.
Resi~ies using in smoking cessation or as a nicotine replacement, the novel nasal ,delivery systems for nicotine herein described could also be useful when it is required to dose nicotine for therapeutic reasons. These include 10 its use as a cognitive enhancer in ulcerative colitis, weight reduction, Parkinsons di~e~e, Alzheimers dise~e, narcolepsy, de~ ssion, sleep a~)noea.
References Benowitz, N.L., Pharmacological aspects of cigarette smoking and nicotine addition. N. Engl. J. Med., 319, 1318 (1988).
Benowitz, N.L., Pharmacokinetic consideration in understanding nicotine dependence, in The Biology of Nicotine Dependence, P 186, Ciba Foundation Symposillm, 152, Wiley Chichester, 1990.
Henningfield, J.E. and Stilzer, M.L (Editors) new Developments in 20 Nicotiine Delivery Systems, Cortlandt Communications, New York 1991.
Illum9 L., Farraj, N.F., Critchley, H and Davis S.S., Nasal administration of gentamicin using a novel microsphere delivery system, Int. J. Pharm, 46 261 (1988).
~ 3~ 24 Illum, L., J0rgensen, H., Bisgaard, H., Krogsgaard, O. and Rossing, N., Bioadhesive microspheres as a potential nasal drug delivery system, Int.
J. Pharm, 39, 189 (1987).
Illum, L., and Davis, S.S., Cellulose micropsheres as a sustained release system for parc,.ler~l administration, Int. J. Pharm, 11, 323 (1982).
Johansson, C.J., Olsson, P., Bende, M., Carlsson, T. and Gunnarsson, P.O., Absolute bioavailability of nicotine applied to different nasal regions, Eur. J. Clin. Pharmacol., 41, 585 (1991).
Russell, M.A.H., Jarvis, M.J., Feyerabend, C and Ferno. O., Nasal 10 nicotine solution, a potential aid to giving up smoking, Br. Med. J. 286, 683 (1983).
Sutherland, G., Stapleton, J.A., Russell, M.A.H., Jarvis, M.J., Hajek, P., Rdc~ er, M., and Feyerabend, C., Randomised controlled trial of nasal nicotine spray in smoking cessation, Lancet, 340, 324 (1992).
15 Codde, J.P., Burton, M.A., Kelleher, D.K., Archer, S.G., and Gray, B.N., Reduced Toxicity of Adriamycin by incorporation into ion-exchange micropheres. A therapeutic study using a rat liver. Anti cancer Res. 10 1715-1718 (1990).
Kwon, G.S., Bae, Y.H., Kim, S.W., Cremers, H and Feijen, J., 20 Preparation and characterisation of microspheres of albumin-heparin conjugates. J. Colloid Interface Sci. 143, 501 (1991).
Sawaya, A., Benoit, J.P., and Benita, S., Binding mechanism of Doxorubicin in ion-exchange albumin microspheres. J. Pharm. Sci. 76 475 25 ~16~0~9 (1987).
Kwon, G.S., Bae, Y.H., Cremers, H., Feijen, J., Kim, S.W., Release of macromolecules from albumin-heparin microspheres, Int. J. Pharm., 79, 191 (1992).
S Cremers, H.P.M., Feijen, J., Kwon, G., Bae, Y.H., Kim, S.W., Noteborn, H.P.J.M., McVie, J.G., Albumin-Heparin Micropheres as CalT,iers for Cytostatic Agents, J. Controlled Rel., 11, 167 (1990).
Claims (13)
1. A nasal drug delivery composition comprising nicotine or a pharmacologically-acceptable derivative or salt thereof, characterised in that the composition is adapted to deliver a pulse of nicotine for rapid absorption and a controlled release of nicotine for subsequent sustained absorption.
2. A composition according to claim 1 which further comprises an ion-exchange material which forms a complex with the nicotine or salt or derivative and provide the controlled release of nicotine.
3. A composition according to claim 2 wherein the ion-exchange material is in the form of microspheres.
4. A composition according to claim 3 wherein the microspheres comprise carboxylated starch alginate or albumin-heparin conjugates.
5. A composition according to claim 3 wherein the microspheres comprise an ion-exchange resin.
6. A composition according to any one of claims 3 to 5 wherein the composition further comprises non ion-exchange microspheres to provide the pulse release of nicotine.
7. A composition according to claim 2 wherein the ion-exchange material is a polymer containing ionizable groups.
8. A composition according to claim 7 wherein the ion-exchange polymer is gellan, alginate or a mixture of alginate and gellan.
9. A composition according to claim 7 or 8 wherein the ion-exchange polymer gels in contact with the nasal mucosa.
10. A composition according to any one of the preceding claims wherein the ion-exchange material is bioadhesive.
11. A composition according to any one of the preceding claims wherein the composition contains sufficient nicotine to overload the ion-exchange material such that the excess nicotine not complexed with the ion-exchange material is delivered as a pulse.
12. A composition according to claim 3 wherein the composition comprises a mixture of ion-exchange microspheres and non-ion-exchange microspheres, the non-ion-exchange microspheres providing the pulse delivery of nicotine and the ion-exchange microspheres providing the controlled release phase.
13. A composition according to claim 1 which comprises nicotine or salt or derivative thereof incorporated in non-ion-exchange bioadhesive microspheres for controlled release together with excess nicotine, which may be adsorbed to the surface of the microspheres, for delivery as a pulse.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9310412.3 | 1993-05-20 | ||
| GB939310412A GB9310412D0 (en) | 1993-05-20 | 1993-05-20 | Nasal nicotine system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2163089A1 true CA2163089A1 (en) | 1994-12-08 |
Family
ID=10735826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002163089A Abandoned CA2163089A1 (en) | 1993-05-20 | 1994-05-20 | Nasal drug delivery composition containing nicotine |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5935604A (en) |
| EP (1) | EP0697858B1 (en) |
| JP (1) | JPH08510467A (en) |
| AT (1) | ATE159425T1 (en) |
| AU (1) | AU685458B2 (en) |
| CA (1) | CA2163089A1 (en) |
| DE (1) | DE69406440T2 (en) |
| DK (1) | DK0697858T3 (en) |
| ES (1) | ES2111304T3 (en) |
| FI (1) | FI955583A (en) |
| GB (2) | GB9310412D0 (en) |
| GR (1) | GR3025890T3 (en) |
| NO (1) | NO306847B1 (en) |
| WO (1) | WO1994027576A1 (en) |
Families Citing this family (78)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9303574D0 (en) * | 1993-11-01 | 1993-11-01 | Kabi Pharmacia Ab | Composition for drug delivery and method of manufacturing thereof |
| GB9414966D0 (en) * | 1994-07-26 | 1994-09-14 | Danbiosyst Uk | Pharmaceutical compositions for the nasal administration of antiviral agents |
| US5876727A (en) * | 1995-03-31 | 1999-03-02 | Immulogic Pharmaceutical Corporation | Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same |
| JP3098401B2 (en) * | 1995-07-12 | 2000-10-16 | 株式会社エルティーティー研究所 | Formulation for nasal administration |
| US5889028A (en) * | 1996-02-09 | 1999-03-30 | Mayo Foundation For Medical Education And Research | Colonic delivery of nicotine to treat inflammatory bowel disease |
| US5846983A (en) * | 1996-02-09 | 1998-12-08 | Mayo Foundation For Medical Education And Research | Colonic delivery of nicotine to treat inflammatory bowel disease |
| AU2340397A (en) * | 1996-03-21 | 1997-10-10 | Mayo Foundation For Medical Education And Research | Use of nicotine to treat liver disease |
| GB9607955D0 (en) * | 1996-04-17 | 1996-06-19 | Tillotts Pharma Ag | Hydrophobic carbomer salt compositions |
| US20070185032A1 (en) * | 1996-12-11 | 2007-08-09 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
| US6391452B1 (en) | 1997-07-18 | 2002-05-21 | Bayer Corporation | Compositions for nasal drug delivery, methods of making same, and methods of removing residual solvent from pharmaceutical preparations |
| EP0898961A1 (en) * | 1997-08-27 | 1999-03-03 | Herta-Maria Dr. Sahlender | Pharmaceutical composition to improve the therapy of acute, postoperative or chronic pain |
| DK1035833T3 (en) * | 1997-12-02 | 2006-01-09 | Archimedes Dev Ltd | Composition for nasal administration |
| FR2771929B1 (en) * | 1997-12-09 | 2001-02-23 | Biovector Therapeutics | USE IN A PHARMACEUTICAL COMPOSITION FOR THE NASAL DELIVERY OF HYDROPHILIC PARTICLES FOR THE DELIVERY OF ACTIVE AGENTS TO THE CENTRAL NERVOUS SYSTEM |
| US7022683B1 (en) | 1998-05-13 | 2006-04-04 | Carrington Laboratories, Inc. | Pharmacological compositions comprising pectins having high molecular weights and low degrees of methoxylation |
| US6344222B1 (en) | 1998-09-03 | 2002-02-05 | Jsr Llc | Medicated chewing gum delivery system for nicotine |
| US20020098264A1 (en) * | 1998-11-27 | 2002-07-25 | Cherukuri Subraman R. | Medicated chewing gum delivery system for nicotine |
| US6358060B2 (en) | 1998-09-03 | 2002-03-19 | Jsr Llc | Two-stage transmucosal medicine delivery system for symptom relief |
| ATE347880T1 (en) * | 1998-10-20 | 2007-01-15 | Univ North Carolina | METHODS FOR MOISTURIZING THE NASAL MUCOSA |
| EP2275133A1 (en) * | 1999-02-26 | 2011-01-19 | Novartis Vaccines and Diagnostics, Inc. | Use of bioadhesives and adjuvants for the mucosal delivery of antigens |
| US20080138294A1 (en) * | 1999-07-16 | 2008-06-12 | Igor Gonda | Systems and methods for effecting cessation of tobacco use |
| US6799576B2 (en) * | 1999-07-16 | 2004-10-05 | Aradigm Corporation | System for effecting smoking cessation |
| US8256433B2 (en) * | 1999-07-16 | 2012-09-04 | Aradigm Corporation | Systems and methods for effecting cessation of tobacco use |
| US20080138398A1 (en) * | 1999-07-16 | 2008-06-12 | Aradigm Corporation | Dual release nicotine formulations, and systems and methods for their use |
| US20080138399A1 (en) * | 1999-07-16 | 2008-06-12 | Aradigm Corporation | Dual release nicotine formulations, and systems and methods for their use |
| WO2001005459A1 (en) * | 1999-07-16 | 2001-01-25 | Aradigm Corporation | System for effecting smoke cessation |
| AT409219B (en) * | 1999-08-13 | 2002-06-25 | Red Bull Gmbh | Use of nicotine for producing pharmaceuticals |
| US8980290B2 (en) | 2000-08-03 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
| US20070225379A1 (en) * | 2001-08-03 | 2007-09-27 | Carrara Dario Norberto R | Transdermal delivery of systemically active central nervous system drugs |
| ATE356636T1 (en) * | 2000-08-03 | 2007-04-15 | Antares Pharma Ipl Ag | COMPOSITION FOR TRANSDERMAL AND/OR TRANSMUCOSAL ADMINISTRATION OF ACTIVE INGREDIENTS WHICH GUARANTEES ADEQUATE THERAPEUTIC LEVELS |
| US7198801B2 (en) * | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
| US7494669B2 (en) * | 2001-02-28 | 2009-02-24 | Carrington Laboratories, Inc. | Delivery of physiological agents with in-situ gels comprising anionic polysaccharides |
| US6777000B2 (en) * | 2001-02-28 | 2004-08-17 | Carrington Laboratories, Inc. | In-situ gel formation of pectin |
| JP2005511477A (en) * | 2001-03-19 | 2005-04-28 | プラエシス ファーマシューティカルズ インコーポレーテッド | Pharmaceutical formulations for sustained release |
| CN101301275A (en) * | 2001-03-26 | 2008-11-12 | 史密丝克莱恩比彻姆公司 | Method for preparing nicotine containing oral dosage form |
| US7458374B2 (en) | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| US20030051728A1 (en) | 2001-06-05 | 2003-03-20 | Lloyd Peter M. | Method and device for delivering a physiologically active compound |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US20040101543A1 (en) * | 2002-03-22 | 2004-05-27 | John Liu | Nicotine-containing oral dosage form |
| US6586449B1 (en) * | 2002-05-28 | 2003-07-01 | Cambrex Charles City, Inc. | Nicotine-containing, controlled release composition and method |
| CA2487712A1 (en) * | 2002-06-28 | 2004-01-08 | Nastech Pharmaceutical Company Inc. | Compositions and methods for modulating physiology of epithelial junctional adhesion molecules for enhanced mucosal delivery of therapeutic compounds |
| US20040105818A1 (en) | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
| US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
| AU2003293987B2 (en) * | 2002-12-20 | 2010-09-09 | Niconovum Ab | A physically and chemically stable nicotine-containing particulate material |
| GB0300531D0 (en) | 2003-01-10 | 2003-02-12 | West Pharm Serv Drug Res Ltd | Pharmaceutical compositions |
| US9119846B2 (en) | 2003-04-29 | 2015-09-01 | Neurim Pharmaceuticals (1991) Ltd. | Method and composition for enhancing cognition in alzheimer's patients |
| IL155666A (en) * | 2003-04-29 | 2013-12-31 | Neurim Pharma 1991 | Composition for treating insomnia |
| MXPA05011644A (en) * | 2003-04-30 | 2005-12-15 | Nastech Pharm Co | CLAUDINSaCOE UNDEREXPRESSION AS MARKERS OF TUMOR METASTASIS. |
| ES2370395T3 (en) | 2003-05-21 | 2011-12-15 | Alexza Pharmaceuticals, Inc. | USE OF A SOLID FUEL LAYER, MANUFACTURING PROCEDURE AND CORRESPONDING HEATING UNIT. |
| EP1646367A4 (en) * | 2003-07-21 | 2011-06-15 | Nesher Solutions Ltd | Gellan gum based oral controlled release dosage forms- a novel platform technology for gastric retention |
| PT1670433E (en) * | 2003-10-10 | 2012-02-08 | Ferring Bv | Transdermal pharmaceutical formulation for minimizing skin residues |
| US7387788B1 (en) | 2003-10-10 | 2008-06-17 | Antares Pharma Ipl Ag | Pharmaceutical compositions of nicotine and methods of use thereof |
| DE602004022708D1 (en) * | 2003-12-02 | 2009-10-01 | Fertin Pharma As | NICOTINE DISPENSER AND MANUFACTURING METHOD |
| US20050129679A1 (en) * | 2003-12-15 | 2005-06-16 | Nastech Pharmaceutical Company Inc. | Method for opening tight junctions |
| US7425340B2 (en) * | 2004-05-07 | 2008-09-16 | Antares Pharma Ipl Ag | Permeation enhancing compositions for anticholinergic agents |
| US20050265955A1 (en) * | 2004-05-28 | 2005-12-01 | Mallinckrodt Inc. | Sustained release preparations |
| US7540286B2 (en) | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| WO2007124250A2 (en) | 2006-04-21 | 2007-11-01 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
| WO2006125642A1 (en) | 2005-05-27 | 2006-11-30 | Antares Pharma Ipl Ag | Methods and apparatus for transdermal or transmucosal application of testosterone |
| KR100699582B1 (en) | 2005-07-11 | 2007-03-23 | 삼성전기주식회사 | Output buffer circuit |
| US9402809B2 (en) | 2006-03-16 | 2016-08-02 | Niconovum Usa, Inc. | Snuff composition |
| NZ571965A (en) * | 2006-03-30 | 2012-02-24 | Engene Inc | Chitosan-based nanoparticles and methods for transfecting gut cells in vivo |
| US8642016B2 (en) | 2006-07-21 | 2014-02-04 | Jsrnti, Llc | Medicinal delivery system, and related methods |
| EP2086317A4 (en) * | 2006-12-01 | 2010-03-03 | Aradigm Corp | Nicotine formulations, kits and systems and methods for their use |
| WO2008067991A2 (en) * | 2006-12-08 | 2008-06-12 | Antares Pharma Ipl Ag | Skin-friendly drug complexes for transdermal administration |
| WO2008112661A2 (en) | 2007-03-09 | 2008-09-18 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
| US20080287507A1 (en) * | 2007-05-16 | 2008-11-20 | John Hedenstrom | Nicotine containing toiletry waters |
| JP2009209086A (en) * | 2008-03-04 | 2009-09-17 | Masami Moriyama | Mucous membrane administration-type vaccine |
| EP2198865B1 (en) | 2008-12-19 | 2011-11-16 | Siegfried Ltd. | Nicotine-containing product |
| WO2011049960A2 (en) * | 2009-10-21 | 2011-04-28 | Otonomy, Inc. | Compositions and methods for the treatment of sinonasal disorders |
| US20110182831A1 (en) * | 2010-01-25 | 2011-07-28 | Aradigm Corporation | Systems and methods used in conjunction with nicotine vaccines for effecting cessation of tobacco use |
| US10130120B2 (en) | 2013-03-15 | 2018-11-20 | Altria Client Services Llc | Use of pectin or other anionic polymers in the stabilization and controlled release of nicotine in oral sensorial tobacco products or nicotine containing non-tobacco oral sensorial products |
| WO2016130908A1 (en) * | 2015-02-13 | 2016-08-18 | The University Of Toledo | Therapeutic polysaccharide midi-gagr and related materials and methods |
| WO2017151651A1 (en) * | 2016-02-29 | 2017-09-08 | Belmont University | Pharmaceutical in situ gelling compositions |
| NZ744942A (en) | 2016-04-12 | 2020-08-28 | Herrera Arturo Solis | Compositions and methods for treating nasal and paranasal mucosa diseases with nicotinic acetylcholine receptor agonists |
| EP3558267B1 (en) * | 2016-12-20 | 2023-04-26 | Fertin Pharma A/S | A mucoadhesive oromucosal formulation comprising a nicotine complex |
| EP3720418B1 (en) * | 2017-12-08 | 2021-08-04 | Fertin Pharma A/S | Nicotine tablet |
| CA3204459A1 (en) * | 2020-12-16 | 2022-06-23 | Liw Innovation Ab | A new powder composition |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2945783A (en) * | 1957-06-20 | 1960-07-19 | Reheis Company Inc | Aluminum protein antacid and process of making |
| US3655866A (en) * | 1970-01-26 | 1972-04-11 | Warner Lambert Co | Sugarless gum containing dicalcium phosphate dihydrate |
| CA1139221A (en) * | 1978-10-10 | 1983-01-11 | Vijay B. Surpuriya | Antacid compositions |
| CA1208558A (en) * | 1982-10-07 | 1986-07-29 | Kazuo Kigasawa | Soft buccal |
| GB2133691B (en) * | 1983-01-21 | 1986-05-21 | Leo Ab | Smoking substitutes for nasal administration |
| IL73912A0 (en) * | 1984-01-09 | 1985-03-31 | Advanced Tobacco Prod | Nicotine preparation |
| US4655231A (en) * | 1984-01-09 | 1987-04-07 | Advanced Tobacco Products, Inc. | Snuff and preparation thereof |
| JPS6115830A (en) * | 1984-06-28 | 1986-01-23 | ザ プロクタ− アンド ガンブル カンパニ− | Antacid composition and manufacture |
| US4971787A (en) * | 1984-08-27 | 1990-11-20 | Warner-Lambert Company | Antacid chewing gum |
| US4882152A (en) * | 1985-12-20 | 1989-11-21 | Yang Robert K | Confectionery delivery system for laxatives, vitamins and antacids |
| DK179687D0 (en) * | 1987-04-08 | 1987-04-08 | Farma Food As | PREPARATION |
| GB8809421D0 (en) * | 1988-04-21 | 1988-05-25 | Fordonal Sa | Antacid compositions with prolonged gastric residence time |
| US5525351A (en) * | 1989-11-07 | 1996-06-11 | Dam; Anders | Nicotine containing stimulant unit |
| SE8904295D0 (en) * | 1989-12-21 | 1989-12-21 | Pharmacia Ab | SMOKING SUBSTITUTE |
| DE4140116A1 (en) * | 1991-12-05 | 1993-06-09 | Bolder Arzneimittel Gmbh | DIMETICON PASTILLES |
| GB9200047D0 (en) * | 1992-01-03 | 1992-02-26 | Univ Alberta | Nicotine-containing nasal spray |
| AU699192B2 (en) * | 1993-08-13 | 1998-11-26 | Bayer Corporation | Hydrolyzed gelatin as a flavor enhancer in a chewable tablet |
| JP3414539B2 (en) * | 1994-05-11 | 2003-06-09 | 有限会社ドット | Composition for nasal absorption |
| WO1996000072A1 (en) * | 1994-06-23 | 1996-01-04 | The Procter & Gamble Company | Treatment of nicotine craving and/or smoking withdrawal symptoms with a transdermal or transmucosal composition containing nicotine and caffeine or xanthine |
-
1993
- 1993-05-20 GB GB939310412A patent/GB9310412D0/en active Pending
-
1994
- 1994-05-20 WO PCT/GB1994/001092 patent/WO1994027576A1/en active IP Right Grant
- 1994-05-20 JP JP7500356A patent/JPH08510467A/en active Pending
- 1994-05-20 CA CA002163089A patent/CA2163089A1/en not_active Abandoned
- 1994-05-20 US US08/553,401 patent/US5935604A/en not_active Expired - Fee Related
- 1994-05-20 DE DE69406440T patent/DE69406440T2/en not_active Expired - Fee Related
- 1994-05-20 GB GB9523372A patent/GB2292316B/en not_active Expired - Fee Related
- 1994-05-20 DK DK94915637.6T patent/DK0697858T3/en active
- 1994-05-20 ES ES94915637T patent/ES2111304T3/en not_active Expired - Lifetime
- 1994-05-20 AU AU67272/94A patent/AU685458B2/en not_active Ceased
- 1994-05-20 AT AT94915637T patent/ATE159425T1/en not_active IP Right Cessation
- 1994-05-20 EP EP94915637A patent/EP0697858B1/en not_active Expired - Lifetime
-
1995
- 1995-11-14 NO NO954582A patent/NO306847B1/en unknown
- 1995-11-20 FI FI955583A patent/FI955583A/en not_active Application Discontinuation
-
1998
- 1998-01-14 GR GR980400063T patent/GR3025890T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU685458B2 (en) | 1998-01-22 |
| JPH08510467A (en) | 1996-11-05 |
| GB2292316A (en) | 1996-02-21 |
| NO954582L (en) | 1995-11-14 |
| ATE159425T1 (en) | 1997-11-15 |
| GB9523372D0 (en) | 1996-01-17 |
| AU6727294A (en) | 1994-12-20 |
| ES2111304T3 (en) | 1998-03-01 |
| FI955583A0 (en) | 1995-11-20 |
| US5935604A (en) | 1999-08-10 |
| FI955583A (en) | 1996-01-19 |
| DK0697858T3 (en) | 1998-05-04 |
| DE69406440T2 (en) | 1998-04-02 |
| EP0697858B1 (en) | 1997-10-22 |
| GB2292316B (en) | 1997-03-26 |
| GB9310412D0 (en) | 1993-07-07 |
| NO306847B1 (en) | 2000-01-03 |
| DE69406440D1 (en) | 1997-11-27 |
| WO1994027576A1 (en) | 1994-12-08 |
| EP0697858A1 (en) | 1996-02-28 |
| GR3025890T3 (en) | 1998-04-30 |
| NO954582D0 (en) | 1995-11-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU685458B2 (en) | Nasal drug delivery composition containing nicotine | |
| CA2312839C (en) | Compositions for nasal administration | |
| EP0739206B1 (en) | Composition for drug delivery comprising nicotine or a derivative thereof and starch microspheres and method for the manufacturing thereof | |
| ES2708552T3 (en) | Method for the preparation of a particulate material containing nicotine with a crystalline cellulose (in particular MCC) | |
| KR100598138B1 (en) | Nicotine inhaler | |
| AU757786B2 (en) | Formulations of fexofenadine | |
| JPH07503481A (en) | Compositions for nasal administration containing polar metabolites of opioid analgesics | |
| JP2002544176A (en) | Compositions for the treatment of diseases of the esophagus | |
| KR100979328B1 (en) | Coated particulate cefuroxime axetil compositions | |
| WO1993000076A1 (en) | Carrier systems for drugs | |
| US20010053359A1 (en) | Drug delivery composition for the nasal administration of antiviral agents | |
| JP2022548626A (en) | nicotine pouch | |
| CA2388395A1 (en) | Compound | |
| WO1996003142A1 (en) | Drug delivery composition for the nasal administration of antiviral agents | |
| EP2266596B1 (en) | Pharmaceutical composition and a method for the production thereof | |
| AU707462C (en) | Drug delivery composition for the nasal administration of antiviral agents | |
| KR20030027422A (en) | A pharmaceutical composition for taste-making cefuroxime axetil and preparation method of thereof | |
| CA2008005A1 (en) | Microencapsulated taste-masked water-insoluble nsaid drug materials |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |