Title:  Compositions for nasal administration

United States Patent:  6,342,251

Assignee:  West Pharmaceutical Services Drug Delivery & Clinical Research Centre (Nottingham, GB)

Filed:  June 2, 2000

Foreign Application Priority Data:   Dec 02, 1997[GB] (9725519); Mar 13, 1998[GB] (9805253)

There is provided a composition for the nasal delivery of a drug suitable for the treatment of erectile dysfunction to a mammal wherein the composition is adapted to provide an initial rise in plasma level followed by a sustained plasma level of the drug.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided a composition for nasal delivery comprising a drug suitable for the treatment of erectile dysfunction, wherein the composition is adapted to provide an initial rise in plasma level followed by a sustained plasma level of the drug.

According to a second aspect of the present invention there is provided a composition for nasal delivery comprising a drug useful in the treatment of erectile dysfunction, e.g. apomorphine or a salt thereof, and one or more excipients, e.g. in the form of anionic or cationic polysaccharides depending on the drug or block copolymers containing ethylene oxide moieties, wherein the composition is adapted to provide an initial rise in plasma level followed by a sustained plasma level of the drug.

It will be apparent to those skilled in the art that some of the drugs described herein as being useful in the treatment of erectile dysfunction are also known to be useful in the treatment of other conditions and that the compositions of the invention containing such drugs could also be used in the treatment of these other conditions. A particular example is apomorphine for treating Parkinson's disease.

With such compositions it is now possible to administer drugs that are suitable for treating erectile dysfunction through the nasal cavity to give a blood level versus time profile of the drug in the systemic circulation that may provide an effective erection in patients with erectile dysfunction, but without significant adverse reactions and side effects. As discussed above, a simple nasal spray containing such a drug is an unsatisfactory dosage form since it provides a high peak level of the drug in the blood initially followed by a rapid decline in this level leading to adverse reactions and poor efficacy.

When drugs are administered using the nasal formulations of the invention, the initial rise in drug plasma level is rapid, although not as rapid as the rise that results when the same drugs are administered using conventional nasal formulations. Moreover, the peak plasma level of drug attained with the nasal formulations of the invention is not as high as that attained with conventional nasal formulations.

By "initial rise in plasma level of the drug" we mean that the peak plasma level will typically be attained in a time less than 45 minutes, preferably in less than 30 minutes and more preferably in less than 15 minutes after nasal application. The peak in the plasma level concentration versus time profile (e.g. in ng/ml) will typically be reduced to 75% or less, preferably 50% or less of the level obtained with an immediate release formulation of the drug, e.g. as is obtained with conventional nasal spray solutions which are not adapted to provide a controlled release effect.

Each drug will have its own particular range of effective concentration depending upon the properties of the drug. For example, for apomorphine the "initial rise in plasma level" of the drug should be to a level between 0.05 and 50 ng/ml, preferably between 0.25 and 10 ng/ml and more preferably between 0.5 and 5.0 ng/ml in less than 30 minutes, preferably in less than 20 minutes and more preferably in less than 10 minutes after nasal application of the composition.

By a "sustained plasma level" of drug we mean that the plasma level is typically maintained at a level that is necessary for a clinical effect (effective concentration) for between 5 and 120 minutes, preferably between 10 and 60 minutes and more preferably between 15 and 45 minutes.

In a preferred embodiment, the plasma level of drug will remain at approximately the level attained after the initial rise in plasma level for between 5 and 120 min, preferably between 10 and 60 min and more preferably between 15 and 45 min.

The drugs which are used in the compositions of the invention may be weakly basic or weakly acidic. By "a weak base" we mean drugs with a pKa less than 10 and by "a weak acid" we mean drugs with a pKa more than 2.5.

Drugs which are suitable for use in the nasal compositions of the invention include alpha-adrenoreceptor antagonists, e.g. phentolamine, phenoxybenzamine, yohimbine, moxislyte delaquamine; compounds with central D₂ -receptor antagonist activity, e.g. apomorphine; compounds that act primarily by blocking the re-uptake of serotonin into nerve terminals, e.g. trazadone and chlorophenylpiperazine; competitive and selective inhibitors of c-GMP type V phosphodiesterases, e.g. sildenafil; L-arginine; and papaverine.

Pharmaceutically acceptable derivatives of the above compounds, such as the pharmaceutically acceptable salts thereof may also be used. A detailed review of these drugs is included in the review entitled Drugs for the Treatment of Impotence by Gascia-Reboll et al. Drugs and Aging 11, 140-151 (1997).

Preferred drugs include those with central D₂ -receptor antagonist activity or the alpha-adrenoreceptor antagonists. Drugs with central D₂ -receptor antagonist activity are of particular interest, especially apomorphine.

A variety of pharmaceutically acceptable excipients can be employed in the compositions of the invention including those that form a complex with or entrap the drug. Particular materials include the polysaccharides and PEGylated block copolymers, i.e. block copolymers containing a block made up of repeating ethylene oxide moieties.

Suitable excipients in the case of liquid compositions include natural polymeric materials, such as sodium alginate, xanthan, gellan gum, welan, rhamsan, agar, carageenan, dextran sulphate, keratan, dermatan, pectin, hyaluronic acid and salts thereof. Modified polysaccharide materials such as carboxymethyl cellulose can also be employed as can block copolymers containing one or more blocks made up of repeating ethylene oxide units. These materials are given as examples and the list is not to be taken as exhaustive.

In one method for preparing liquid compositions, the excipient material such as a polysaccharide or a block copolymer containing ethylene oxide moieties is dissolve in ultrapure water or a buffer system or in ultrapure water to which has been added various salts such as sodium chloride. The solution is stirred overnight or until the material has dissolved. With apomorphine, the drug may be dissolved in a similar aqueous system and added to the solution of the excipient material. Alternatively, the apomorphine may be dissolved directly in the excipient solution. A suitable concentration of apomorphine in the final liquid composition is in the range of from 1 mg/ml to 200 mg/ml, preferably in the range of from 2 mg/ml to 100 mg/ml and more preferably in the range of from 5 mg/ml to 50 mg/ml. The concentration of excipient material needed is dependent on the type of material used but is typically between 0.01% w/v and 50% w/v, by which we mean from 0.01 to 50 g of excipient per 100 mls of the liquid, e.g. water. A preferred concentration of the excipient material is in the range 0.1% w/v to 50% w/v, i.e. 0.1 to 50 g of excipient per 100 mls of the liquid, more preferably in the range 0.5% w/v to 50% w/v and particularly in the range 1.0% w/v to 30% w/v.

For powder compositions, it is possible to use carboxylated starch microspheres or positively charged microspheres available from Perstorp (Sweden) and microspheres produced from natural polymers such as carboxylmethyl cellulose, sodium alginate and chitosan.

In one method for preparing powder systems, microspheres having a mean diameter of between 0.5 .mu.m-300 .mu.m are suspended in water or in water containing the dissolved drug and the formulation freeze dried. If the microspheres are suspended in pure water, then the drug is added to this suspension prior to freeze dying. With apomorphine, the final concentration of apomorphine per mg of microsphere is typically between 0.01 mg/mg and 5.0 mg/mg, preferably between 0.02 mg/mg and 2.5 mg/mg and more preferably between 0.025 mg/mg and 0.25 mg/mg. Weight ratios of drug to microspheres in the range of from 1 part drug to 5 to 10 parts of the microspheres are especially preferred.

In another method for preparing powder systems in the form of microspheres, the drug such as apomorphine and the microspheres are mixed mechanically in the dry state.

When drugs other than apomorphine are employed, the above processes and amounts may be modified readily in accordance with techniques well known to those skilled in the art.

It would also be possible to freeze dry a liquid composition for reconstitution before use by the addition of water.

Preferred excipient materials for liquid compositions include pectin, gellan gum, alginate, welan, rhamsan, xanthan and carageenan, particularly pectin, gellan gum, alginate, welan and rhamsan and especially pectin and gellan gum.

Gellan gum is the deacetylated form of the extracellular polysaccharide from Pseudomonas elodae. Native/high-acyl gellan is composed of a linear sequence of tetra-saccharide repeating units containing D-glucuronopyranosyl, D-glucopyranosyl and L-rhamnopyranosyl units and acyl groups.

Alginate is composed of two building blocks of monomeric units namely .beta.-D-mannuronopyranosyl and .alpha.-guluronopyranosyl units. The ratio of D-mannuronic acid and L-guluronic acid components and their sequence predetermines the properties observed for alginates extracted from different seaweed sources.

Welan is produced by an Alcaligene species. Welan has the same basic repeating unit as gellan but with a single glycosyl sidechain substituent. The side unit can be either an .alpha.-L-rhamnopyranosyl or an .alpha.-L-mannopyranosyl unit linked (1->3) to the 4-0-substituted .beta.-D-glucopyranosyl unit in the backbone.

Rhamsan is produced by an Alcaligenes species. Rhamsan has the same repeating backbone unit as that of gellan but with a disaccharide sidechain on 0-6 of the 3-O-substituted .beta.-D-glucopyranosyl unit. The side chain is a .beta.-D-glucopyranosyl-(1-6)-.alpha.-D-glucopyranosyl unit.

Xanthan is produced by a number of Xanthomonas strains. The polymer backbone, made up of (l->4)-linked .beta.D-glucopyranosyl units is identical to that of cellulose. To alternate D-glucosyl units at the 0-3 position, a trisaccharide side chain containing a D-glucoronosyl unit between two D-mannosyl units is attached. The terminal .beta.-D-mannopyranosyl unit is glycosidically linked to the 0-4 position of the .beta.-D-glucopyranosyluronic acid unit, which in turn is glycosidically linked to the 0-2 position of an .alpha.-D-mannopyranosyl unit.

Carageenan is a group of linear galactan polysaccharides extracted from red seaweeds of the Gigartinaceae, Hypneaceae, Solieriaceae, Phyllophoraceae and Furcellariaceae families.

Pectin is an especially preferred material and is obtained from the dilute acid extract of the inner portion of the rind of citrus fruits or from apple pomace. It consists of partially methoxylated polygalacturonic acids. The gelling properties of pectin solutions can be controlled by the concentration of the pectin, the type of pectin, especially the degree of esterification and the presence of added salts.

Mixtures of excipients can also be used, such as mixtures of pectin or gellan with other polymers such as alginate, gelling of the mixture being caused by the pectin or gellan gum. Other combinations of gums can also be used, particularly where the combination gives a synergistic effect, for example in terms of gelation properties. An example is xanthan--locust bean gum combinations.

A preferred excipient for liquid compositions is one that allows the composition to be administered as a mobile liquid but in the nasal cavity will cause the composition to gel, thereby providing a bioadhesive effect which acts to hold the drug at the absorptive surface for an extended period of time. The anionic polysaccharides pectin and gellan are examples of materials which when formulated into a suitable composition will gel in the nasal cavity owing to the presence of cations in the nasal fluids.

The liquid compositions comprising pectin or gellan will typically comprise from 0.01 to 20% w/v of the pectin or gellan in water or an aqueous buffer system, by which we mean that the pectin or gellan will be present in an amount of from 0.01 to 20 g per 100 mls of water or aqueous buffer. A preferred concentration for the pectin or gellan in the water or aqueous buffer is in the range of from 0.1% to 15% w/v, more preferably 0.1 to 5.0% w/v and particularly 0.2% to 1% w/v.

For gelling to occur in the nasal cavity with a liquid composition comprising an excipient which gels in the presence of ions, such as pectin or gellan gum, it is likely to be necessary to add monovalent and/or divalent cations to the composition so that it is close to the point of electrolyte induced gelation. When such a composition is administered to the nasal cavity, the endogenous cations present in the nasal fluids will cause the mobile liquid composition to gel. In other words, the ionic strength of the composition is kept sufficiently low to obtain a low viscosity formulation that is easy to administer, but sufficiently high to ensure gelation once administered into the nasal cavity where gelation will take place due to the presence of cations in the nasal fluids.

Suitable cations for adding to the composition include sodium, potassium, magnesium and calcium. The ionic concentrations are chosen according to the degree of gelling required, and allowing for the effect that ionised drug present may have on gelling since certain drug molecules that are weakly basic and positively charged such as apomoxphine will also act as monovalent cations and will tend to have an effect on the gelling properties of the pectin or gellan system. For example, for a liquid composition comprising 0.2% w/v of gellan, i.e. 0.2 g of gellan per 100 mls of liquid, the divalent ions calcium and magnesium 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 concentration of each cation is required to induce gelation.

The ionic strength for a liquid nasal composition comprising 0.5% w/v of pectin or gellan gum can be in the range of 0.1 mM-50 mM for monovalent cations with the preferred range being 1 mM-5 mM and in the range of 0.1 mM-5 mM for divalent cations with the preferred range being 0.15 mM to 1 mM. For higher concentrations of pectin or gellan gum the ionic strengths should be lowered accordingly. The cations will compete with a positively charged drug such as apomorphine for binding with the anionic polysaccharide and the concentration of cations should be controlled so that a sufficient amount of positively charged drug will bind with the ion-exchanged anionic polysaccharide.

The complex between a basic drug such as apomorphine and the ion-exchange anionic polysaccharide forms as a result of ionic interaction between the negatively charged polysaccharide and the positively charged drug. The pH of the composition must therefore be such that the two species are well ionised. With apomorphine, the pH should be kept in the range of from pH 3 to pH 8, preferably in the range of from pH 4 to pH 6, by the presence of appropriate buffers or acids. For these ion-exchange polysaccharides, the positively charged drug such as apomorphine can be added either as the base or as a salt. When the drug is used in its salt form it will tend to ionise once in an aqueous environment and if it is in base form the pH of the system can be controlled by the addition of appropriate acids so as to ensure that the drug is ionised and able to interact with the polysaccharide.

Block copolymers such as a poloxamer (polyoxyethylene-polyoxypropylene block copolymer) or a block copolymer of polylactic acid and polyoxyethylene (PLA-PEG) may also be used as the excipient in liquid compositions. The poloxamers can be obtained from BASF as the Pluronic.TM. and Tetronic.TM. series with different molecular weights and block structures. A preferred block copolymer is Pluronic.TM. F127 also known as Poloxamer 407.

Other polymers which may be used as an excipient include PLA-PEG copolymers which can be synthesised by the methods described in EP-A-0166596 or by the methods described by Deng et al (J. Polymer Sci. Part C Polymer letters, 24, 411, 1988), Zhu et al. (J. Polym. Sci. Polm. Chem. 27,2151, 1989) or Gref et al (Science,263, 1600, 1994),PCT/WO95/03357. Water soluble linear tri-block copolymers of PLA-PEG that gel when the temperature is raised are especially preferred. These are described by Jeong et al. Nature. 388, 860, 1997. A suitable concentration of the block copolymer in the liquid formulation is from 5 to 50% w/v, by which we mean from 5 to 50 g of copolymer per 100 mls of the liquid, e.g. water, with a concentration between 10 and 30% w/v being particularly preferred.

The liquid nasal compositions of the invention can also contain any other pharmacologically-acceptable, non-toxic ingredients such as preservatives, antioxidants and flavourings. Benzalkonium chloride may be used as a preservative. It is o known that apomorphine can demonte instability, probably due to auto-oxidation. Thus, stabilising agents such as sodium metabisulphite or ascorbic acid can be included in the compositions.

When the formulations according to the present invention are in the form of microspheres, polysaccharide microspheres may be used including those which carry suitable anionic groups such as carboxylic acid residues, carboxymethyl groups, sulphopropyl groups and methylsulphonate groups or cationic groups such as amino groups. Carboxylated starch microspheres are especially preferred. Carboxylated starch microspheres (Cadexomer.TM.) are available from Perstorp (Sweden).

Other suitable materials for the microspheres include hyaluronic acid, chondroitin sulphate, alginate, heparin and heparin-albumin conjugates, as described in Kwon et al. (Int. J. Pharm. 79, 191, 1991).

Further materials that may be used for the microspheres include carboxymethyl dextran (e.g. CM Sephadex.TM.), sulphopropyl dextran (e.g. SP Sephadex.TM.), carboxymethyl agarose (e.g. CM Sepharose.TM.), carboxymethyl cellulose, cellulose phosphate, sulphoxyethyl cellulose, agarose (e.g. Sepharose.TM.), cellulose beads (e.g. Sephacel .TM.) and dextran beads (e.g. Sephadex .TM.) which are all available from Pharmacia, Sweden.

The term microsphere as used herein refers particularly to substantially spherical particles which can be a monolithic solid sphere or a small capsule. To ensure correct deposition in the nasal cavity, the microspheres preferably have a mean diameter of between 0.5 and 250 .mu.m, preferably between 10 .mu.m and 150 .mu.m and more preferably between 10 and 100 .mu.m as measured using a conventional light microscope.

Microspheres can be made by procedures well known in the art including spray drying, coacervation and emulsification (see for example Davis et al. Microsphere and Drug Therapy, Elsevier, 1984; Benoit et al. Biodegradable Microspheres: Advances in Production Technologies, Chapter 3, Ed. Benita, S, Dekker, New York, 1996; Microencapsulation and related Drug Processes, Ed. Deasy, Dekker, 1984, New York, pp 82, 181 and 225; U.S. Pat. No. 2,730,457 and U.S. Pat. No. 3,663,687).

In the spray drying process, the material used to form the body of the microsphere is dissolved in a suitable solvent (usually water) and the solution spray dried by passing it through an atomisation nozzle into a heated chamber. The solvent evaporates to leave solid particles in the form of microspheres.

In the process of coacervation, microspheres can be produced by interacting a solution of a polysaccharide carrying a positive charge with a solution of a polysaccharide carrying a negative charge. The polysaccharides interact to form an insoluble coupling that can be recovered as microspheres.

In the emulsification process, an aqueous solution of the polysaccharide is dispersed in an oil phase to produce a water in oil emulsion in which the polysaccharide solution is in the form of discrete droplets dispersed in oil. The microspheres can be formed by heating, chilling or cross-linking the polysaccharide and recovered by dissolving the oil in a suitable solvent.

The microspheres can be hardened before combining with the drug by well known cross-inking procedures such as heat treatment or by using chemical cross-linking agents. Suitable agents include dialdehydes, including glyoxal, malondialdehyde, succinicaldehyde, adipaldehyde, glutaraldehyde and phthalaldehyde, 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 converts compounds with nucleophilic centres such as amino or hydroxyl to epoxide derivatives. The cross-linkers used for ion-exchange microspheres should not be directed towards the negatively or alternatively positively charged groups required for binding the drug.

For microsphere compositions of the invention, the drug such as apomorphine is preferably in salt form to ensure that it is ionised. The drug is sorbed to the microspheres by admixing with the microspheres after their formation. This may be achieved by suspending the microspheres in an aqueous buffer and then adding the drug in solution. The microspheres can then be recovered by a process of freeze drying.

The drug can be combined with the microspheres at different ratios. A quantity of microspheres greater than that of the drug on a weight to weight basis is preferred. The amount chosen will be dictated by the dose of the drug and the complexation properties of the microsphere.

It is possible to control the shape of the plasma level time profile by the amount of anionic or cationic polysaccharide material or polymer that is added to the nasal formulation containing the drug useful in erectile dysfunction. Taking apomorphine as the drug, a plasma level suitable for the treatment of erectile dysfunction is believed to be from 0.5 to 5.0 ng/ml. The duration of effect should be from 15 to 30 minutes. A suitable nasal dose of apomorphine will be between 0.5 and 5.0 mg. A preferred nasal dose will be between 1.0 and 3.0 mg.

The formulation, if in the form of a liquid, can be administered using a simple nasal spray device available from companies such as Valois or Pfeiffer.

Microspheres or other powder formulations can be administered using a powder device. Suitable powder devices are available from Bespak in the United Kingdom. Other suitable powder devices are the nasal insufflators used for drugs such as Rhinocort.TM. (marketed by Teijin in Japan). The device from Direct Haler (Denrmark) can also be used. Such nasal devices can be passive with the patient having to draw a dose of the powder into the nasal cavity from the device through their own inspiration or active with powder being blown into the nasal cavity through some mechanical process, e.g. using a rubber bulb or spring system.

Claim 1 of 35 Claims

We claim:

1. A composition for nasal delivery comprising a drug suitable for the treatment of erectile dysfunction and one or more excipients, wherein;

1) the composition is either a liquid or a powder;

2) at least one or more excipients selected from the group consisting of block copolymers comprising repeating ethylene oxide moieties, anionic polysaccharides and ion exchange polymeric materials; and

3) the composition is adapted to provide an initial rise in plasma level followed by a sustained plasma level of the drug.

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