Patent 6,238,689

A delayed and sustained release composition of an additive and/or toxic agent such as nicotine is delivered systemically in therapeutic amounts while avoiding the peak plasma levels which gives rise to addiction and/or toxic side effects. The composition is delivered for absorption predominantly from the colon.

Description of the Invention

The present invention relates to the use of nicotine composition delivered for absorption from the intestine, particularly the ileum and colon, for the treatment of nicotine responsive conditions particularly schizophrenia, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, depression (particularly associated with cessation of smoking), inflammatory skin conditions, and as an aid to cease smoking.

Cigarette smoking has been reported as altering the inflammatory response in the skin following application of irritants and rubefacients (Mills et al, BMJ 1993;307:911). In a follow up study, Mills administered nicotine via a transdermal delivery system and was found to suppress the cutaneous inflammatory response to sodium lauryl sulphate (irritant) and UVB radiation, as well as reactive hyperaemia following arterial occlusion (Workshop on Nicotine as a Therapeutic Agent--May 15, 1996, Frankfurt, Germany). In the same workshop, Sandberg et al reported that administration of nicotine (either 2 mg nicotine gum or 7 mg transdermal nicotine patch) along with neuropleptics produce a decrease in tic symptoms in patients suffering from Tourette's syndrome. A beneficial response of Alzheimer's and Parkinson's disease patients to nicotine was also reported at the workshop.

However, nicotine has a substantial effect on the cardiovascular system including increased heart rate and blood pressure resulting in greater myocardial work and oxygen requirement and coronary vasocontriction. Nicotine has also be purported to activate platelets and to adversely affect blood lipids, thereby promoting atherosclerosis and increasing the risk of acute coronary events. Furthermore nicotine from tobacco products has also been associated with an increased risk of cancer and cerebral haematoma.

Known delivery routes for nicotine are via cigarette smoking, inhalers, nasal spray, polyacrylic gum and transdermal patch. Inhalers and nasal sprays deliver nicotine rapidly to the blood plasma in high peak concentrations and can therefore give rise to addictive cravings similar to cigarette smoking. The use of nicotine gum and transdermal patches are reported at the aforementioned Nicotine Workshop, and are used extensively to aid in the cessation of smoking. However long term administration of a nicotine patch is limited by a relatively high rate of dermatological side effects, especially in the elderly. Patients have also reported side effects such as nausea, headaches, tremor and vomiting, thereby again limiting patient compliance. Polyacrylic gum again relies heavily on good patient compliance. The amount of nicotine delivered depends on the rate and length of chewing and therefore it is difficult to achiever a controlled uniform plasma concentration of nicotine.

It is an object of the present invention to obviate or mitigate the aforesaid disadvantages.

It is a further object to provide for delivery of nicotine which is convenient and where side effects of nicotine is limited, while still providing a beneficial effect on conditions susceptible to treatment with nicotine.

The inventors have now found that the blood plasma concentration of nicotine can be controlled to therapeutic levels while limited the adverse side-effects if nicotine is absorbed from the small or large intestine. For example nicotine can be delivered rectally, such as by an enema, to the large intestine or as a post-gastric delayed release oral (DRO) composition to the small and/or large intestine. In this way the nicotine is absorbed more slowly into the blood plasma over a sustained time period thereby decreasing the peak plasma concentrations which typically induces nicotine dependency. It also avoids the dermatological side-effects of a transdermal patch, and the uncertain effectiveness of nicotine chewing gum. Thus therapeutic levels of nicotine can be delivered to treat the aforementioned conditions while reducing the adverse side-effects normally associated with nicotine.

Accordingly in a first aspect of the invention there is provided the use of nicotine or a pharmacologically acceptable derivative or metabolite thereof in the preparation of a medicament which is adapted for absorption from the small and/or large intestine for the treatment or prophylaxis of inflammatory skin conditions, schizophrenia, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, depression, or to assist in the cessation of smoking. In fact, nicotine could be used therapeutically in any disease state in which an association with non-smoking or smoking status would suggest a therapeutic role for nicotine. For the avoidance of doubt, absorption from the small and/or large intestine includes from the pylorus to the anus.

Examples of inflammatory skin conditions susceptible to the invention are acne, reigacne vulgaris and rosacea. With Alzheimer's patients, the invention will typically improve their attentional function. Depression, particularly associated with the cessation of smoking, is susceptible to treatment with the invention.

A further aspect of the invention comprises a method for the treatment of nicotine responsive condition, disclosed herein, comprising administering to the patient an effective amount of a rectally administrable or delayed release oral (DRO) DRO composition as defined in the first aspect of the invention.

Co-pending International No. PCT/GB97/00369 and U.S. application Ser. Nos. 08/605,319 and 08/794,668 relate to the use of nicotine delivered for sustained release from the colon for the treatment of inflammatory bowel disease, and therefore this nicotine responsive condition is not within the scope of the present condition.

Although there is some benefit in having absorption of nicotine from anywhere in the small or large intestine, it is most preferred that absorption occurs predominantly in the colon. This in the case of a post-gastric delayed release oral (DRO) composition, the composition will pass through the small intestine in about 4 to 8 hours and will then reside in the colon for about 48 hours. Furthermore nicotine is absorbed more slowly in the colon than in the small intestine. Therefore nicotine delivered for absorption predominantly in the colon will be absorbed more slowly over a sustained period and will give rise to a more uniform blood plasma concentration, and will reduce the peak concentration of nicotine which otherwise cause dependence and adverse side-effects.

By predominant absorption from the colon, we mean to include at least 70%, more preferably at least 80%, such as at least 85% or at least 90% of the total dose of nicotine.

In a preferred embodiment, a DRO composition is delivered for dissolution in the ileum, more particularly the terminal ileum so that most of the nicotine would be released and absorbed in the colon.

The most preferred form of the invention is a sustained and post-gastric delayed released composition. In this form, the effect of the nicotine being absorbed more slowly and at more uniform concentration levels into the bloodstream from the small and/or large intestine, is enhanced because the composition also controls the release of the nicotine over a sustained time interval. This form of the invention is of particular benefit, where most of the nicotine is released and absorbed in the colon i.e. the composition resides here for the longest time period. Thus in a preferred embodiment the invention relates to use of nicotine given orally as a sustained release DRO composition (advantageously having an enteric coating) for the treatment of nicotine responsive conditions.

Various sustained release compositions of nicotine are described later and include nicotine being present as a nicotine-polyacrylate complex, nicotine is an ampiphilic polyglycolized glyceride matrix, and using various enteric coated microgranules containing nicotine in an enteric coated capsule. A preferred form of saturated polyglycolized glyceride is Gelucire.TM., particular Gelucire 44/14 and 53/10.

By pharmacologically acceptable derivatives and metabolites of nicotine we mean derivatives which exhibit pharmacotherapeutic properties similar to said active agent. This includes pharmacologically acceptable salts, esters and salts of such esters.

Any pharmacologically acceptable derivative or metabolite of nicotine which exhibits pharmacotherapeutic properties similar to nicotine may be used in practising the invention. Such derivatives and metabolites are known in the art (Glenn et al J. Org. Chem., 43:2860-2870 (1978); Dominiak et al., Klin Wochenschr, 63:90-92 (1985)) and include nicotine oxide and cotinine.

A particular characteristic property of nicotine is its ability to form salts with almost any acid and double salts with many metals and acids. The acids that may be used to prepare the pharmaceutically acceptable acid salts of nicotine are those that form non-toxic acid salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, succinate, maleate, fumarate, bitartrate, gluconate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluene sulphonate, camphorate and pamoate salts. Particularly preferred are the tartrate and bitartrate salts.

Preferably nicotine is present in a complex with a polyacrylic acid polymer to form a nicotine-polyacrylate complex, preferably a water-soluble complex.

Preferably, the polyacrylate is a carbomer, such as those described in the British Pharmacopoeia and defined in CAS 54182-57-9. Carbomers are synthetic high molecular weight polymers of acrylic acid cross-linked with allylsucrose, and contain 56 to 68% carboxylic acid groups. When used in accordance with an oral dosage form of the invention the carbomers hydrate and swell to form a gel, which retards the nicotine release and absorption.

A complex of bismuth and carbomer is disclosed in EP-A-0540613.

Convenient modes of administration to deliver the sustained release composition for absorption from the colon are rectal compositions such as enemas and suppositories, and DRO compositions such as enteric coated tablets, capsules, powder or granules.

Typical enema formulations comprise an effective amount of nicotine dissolved or dispersed in a suitable aqueous flowable carrier vehicle. The carrier vehicle is preferably thickened with natural or synthetic thickeners such as gums, acrylates or modified celluloses. The formulation can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, e.g. a tris-fatty acid glycerate or lecithin. Nontoxic nonionic surfactants can also be included as wetting agents and dispersants. Unit dosages of enema formulations can be administered from prefilled bags or syringes. The carrier vehicle may also comprise an effective amount of a foaming agent such as n-butane, propane or i-butane. Such formulations can be delivered from a preloaded syringe pressurised container, so that the vehicle is delivered to the colon as a foam, which inhibits its escape from the target site.

A dosage form of nicotine adapted for either rectal or oral delivery may also be complexed with a suspending or thickening agent to prolong release of the dosage form of nicotine. Such agents include methacrylic acid polymer or acrylic acid polymers, preferably carbomers (carboxypolymethylene) which are synthetic high molecular weight acrylic acid polymers crosslinked with polyfunctional moieties such as polyallylsucrose. Generally, carbomers comprise 50 to 70% carboxylic acid groups.

In a preferred embodiment, an active agent/carbomer complex may be administered rectally as liquid enemas. Liquid enemas are prepared essentially as described above by forming an effective amount of a nicotine/carbomer complex in a suitable flowable liquid carrier. The carrier vehicle is preferably thickened with thickeners and can also comprise an effective amount of a lubricant. Unit dosages of enema formulations can be administered from prefilled bags or syringes.

The pH of the enema should be 3.0 to 3.5 before a buffering solution is added to raise the pH to between 4.5 to 5.5, ideally about pH 5.0 (at which patients feel comfortable).

In a carbomer formulation this can be achieved by adding quantities of a suitable amine protein acceptor to the preparation. At the same time such a preparation also neutralises some of the carbomer molecules thereby increasing the viscosity. Preferably trometamol is used as a buffering and thickening agent in an enema composition. On average each 100 ml of enema requires about 6 ml (viscosity 4.5 to 7.5 mNm) of a 1% solution of trometamol to give a final acceptable pH of about 5 and viscosity of 3 to 6.5 mNm, ideally 4.0 mNm.

In general where the nicotine is administered rectally, a suitable dose will be in the range of from 0.001 to 1.5 mg/Kg, preferably in the range of 0.01 to 0.20 mg/Kg, most preferably in the range of 0.04 to 0.10 mg/Kg, calculated as nicotine in the free base form. Preferably, nicotine is rectally administered once or twice daily.

When the active agent is administered orally via a tablet, capsule or granules, preferably the dosage form will have an enteric coating which dissolves in the ileum so that the active agent can predominantly be absorbed from the colon.

In general, where the nicotine is administered orally, a suitable dose will be in the range of from 0.001 to 1.5 mg per day preferably in the range of 0.01 to 20 mg per day most preferably in the range of 0.04 to 15 mg per day, calculated as nicotine in the free base form. Preferably, nicotine is orally administered 1 to 4 times daily, for example 3-4 times daily, although more frequent dosing is contemplated where hourly dosing is desired.

The compound is conveniently administered orally in unit dosage form; for example, containing 1 to 36 mg, conveniently 3 to 30 mg, such as 6 to 30 mg, and such as 15 to 30 mg of active ingredient per unit dosage form. In a preferred embodiment of the invention 3 mg to 6 mg was useful.

An effective amount of nicotine can be administered to the intestine, preferably the colon of the patient by oral ingestion of a unit dosage form such as a pill, tablet, powder or capsule, comprising an effective amount of nicotine which is enterically coated so as to be released from the unit dosage form in the lower intestinal tract, e.g., in the ileum and in the colon of the patient. Enteric coatings remain intact in the stomach, but will dissolve and release the contents of the dosage form once it reaches the region where the pH is optimal for dissolution of the coating used. The purpose of an enteric coating is to substantially delay the release of the nicotine until it reaches its target site of action in the ileum or colon.

Thus, a useful enteric coating is one that remains intact in the low pH environment of the stomach, but readily dissolved when the optimum dissolution pH of the particular coating is reached. This can vary between pH 3 to 7.5 depending upon the chemical composition of the enteric coating, but is preferably between about pH 6.8 and pH 7.2. The thickness of the coating will depend upon the solubility characteristics of the coating material and the site to be treated.

In general coating thicknesses of about 25 to 200 .mu.m, and especially 75 to 150 .mu.m, are preferred using about 3 to 25 mg, preferably 8 to 15 mg of acidic coating material per cm² of tablet or capsule surface. The precise coating thickness will however depend upon the solubility characteristics of the acidic material used and site to be treated.

When used in accordance with an oral dosage form of the invention the carbomers hydrate and swell to form a gel, which retards the nicotine release and absorption.

The most extensively used polymer for enteric coating is cellulose acetate phthalate (CAP). However, CAP has an optimum dissolution pH greater than 6, thus early drug release may occur. Another useful polymer is polyvinyl acetate phthalate (PVAP) which is less permeable to moisture and gastric fluid, more stable to hydrolysis and able to dissolve at a lower pH, which could also result in early release of nicotine in the duodenum.

Another available polymer is hydroxypropyl methylcellulose phthalate. This has similar stability to PVAP and dissociates in the same pH range. Further examples of currently used polymers are those based on methacrylic acid, e.g., methacrylic acid ester copolymers with acidic ionizable groups, such as Eudragit L (particularly L30D) and S (methacrylic acid copolymer) and mixtures thereof. Dosage forms coated with Eudragit.TM., which dissolve in the ileum at about pH 6.8, and in the terminal ileum and caecum at about pH 7.2, have been developed for delivery of 5-aminosalicylic acid, and are particularly preferred in accordance with the invention. These coatings will deliver most of the active for absorption in the colon, although some will be absorbed at the site of dissolution of the coating (e.g. terminal ileum and/or caecum).

In a preferred embodiment a capsule is enteric coated and contains a plurality of granules containing the active agent which also are enterically coated. The enteric capsule coating is insoluble in the pH medium of the stomach, but dissolves in the pH of the small intestine, preferably the ileum, to release the enterically coated granules. These coated granules are insoluble in intestinal juice below about pH 7, but are soluble in colonic intestinal juice. The beads have different enteric coated polymers and thicknesses of coatings to provide a sustained release of the active agent for absorption from the colon. Suitable coatings are Eudragit L, S, R, L, RL and RS. A capsule such as above is described in more detail in U.S. Pat. No. 5,401,512 and WO-A-9214452, the teachings of which are incorporated herein by reference.

In another preferred oral dosage form, the active agent is complexed with a carbomer which is itself coated with an acrylic resin and contained in an enterically coated capsules. The capsule coating dissolves in the intestinal juices such as those of the small intestine, preferably the ileum, to deliver the active agent/carbomer complex to the colon.

A suitable alternative formulation would be to incorporate the nicotine or its salts, more preferably the nicotine carbomer complex, into heat-meltable ampiphilic excipients such as partial glycerides and polyglycerides of fatty acids of the Gelucire.TM. type (available from Gattefosse, France) or polyoxyethylene glycols, filled into hard gelatine capsules and coated with either cellulose derivative or acrylic polymer enteric coating.

Carbomers are available as fine white powders which disperse in water to form acidic colloidal suspensions (a 1% dispersion has approx. pH 3) of low viscosity. Neutralisation of these suspensions using a base, for example sodium, potassium or ammonium hydroxides, low molecular weight amines and alkanolamines, results in the formation of clear translucent gels. Nicotine and its salts form stable water-soluble complexes with carbomers at about pH 3.5 and are stabilised at an optimal pH of about 5.6.

Preferably, the carbomer is Carbopol. Such polymers are commercially available from B. F. Goodrich under the designation Carbopol.TM. 420, 430, 475, 488, 493, 910, 934, 934P, 974 and 974P. Carbopols are versatile controlled-release polymers, as described by Brock (Pharmacotherapy, 14;430-7(1994)) and Durrani (Pharmaceutical Res. (Supp.) 8;S-135 (1991)), and belong to a family of carbomers which are synthetic, high molecular weight, non-linear polymers of acrylic acid, crosslinked with polyalkenyl polyether. In a particularly preferred embodiment the carbomer is Carbopol.TM. 974P NF.

To prepare, for example, a nicotine/carbomer complex the carbomer is suspended in a appropriate solvent, such as water, alcohol or glycerin. Preferably, the carbomer is mixed with water, preferably de-ionised water. Mixtures may range, for example from 0.002 to 0.2 g of carbomer per ml of solvent, preferably from 0.02 to 0.1 g of carbomer per ml of solvent. The mixture is stirred thoroughly at room temperature until a colloidal suspension forms. The dispersion may be stirred using a suitable mixer with a blade-type impeller, and the powder sieved into the vortex created by the stirrer using a 500 micron brass sieve. This technique allows ample wetting of the powder and prevents the powder from forming a cluster of particles which then become difficult to wet and disperse.

The nicotine or nicotine salt may be diluted with any pharmaceutically acceptable organic solvent. In a preferred embodiment, the solvent is an alkanol such as ethanol. Mixtures may range, for example, from 0.01 to 10 g of nicotine per ml of solvent, preferably from 0.5 to 5 g of nicotine per ml solvent. This solution is then added drop wise to the carbomer suspension and mixed continuously until a gel of uniform consistency has formed. Preferably, the nicotine/complex is made by combining 1 g of nicotine or nicotine salt with from 0.1 to 100 g of carbomer, more preferably with 1 to 50 g of carbomer. A gradual thickening of the suspension occurring as neutralisation of the carbomer takes place. The preparation will now take on the appearance of a slightly white translucent gel. This physical change in viscosity and appearance is consistent with neutralisation of the acid by the base.

The gel is then dried. According to one embodiment, the gel is vacuum dried. By way of example, the gel is spread on a glass plate and dried under vacuum at 50^oC. for about 24 hours. Alternatively, the gel may be freeze-dried. Such methods are well known in the art.

Nicotine/carbomer complexes can then be formed into solid dosage forms and a pharmaceutically acceptable coating may be applied, as described above for non-complexed nicotine. For example, the complex may be enterically coated thereby delaying the release of the nicotine/carbomer complex until it reaches the ileum and colon.

Alternatively the gel can be incorporated into a suitable liquid enema formulation as described earlier.

Claim 1 of 12 Claims

What is claimed is:

1. In a method for treating a nicotine-responsive condition which is not inflammatory bowel disease comprising administering to a patient an effective amount of an active compound selected from the group consisting of pharmacologically acceptable derivatives of nicotine, the improvement which comprises administering to the patient as a post-gastric delayed release oral composition a unit dosage form which is a pill, tablet, powder or capsule containing an effective amount of about 1 to about 36 mg per unit dosage form of a pharmacologically acceptable nicotine salt or nicotine polyacrylate complex which is enteric coated with polymer so as to be released at intestinal pH.

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