JP2006502972A - Orally dispersible pharmaceutical formulation of desmopressin - Google Patents

Abstract

Good bioavailability of desmopressin can be obtained with an orally dispersible pharmaceutical formulation that allows rapid intraoral dispersion of the active substance. As a result, desmopressin can be absorbed from the gastrointestinal tract under the tongue, buccal and / or gingival mucosa and / or for systemic distribution. Preferred formulations include desmopressin and an open matrix network that is a water soluble or water dispersible inert carrier material. The desmopressin thus formulated is useful for postponement of excretion, incontinence, primary nocturnal urine (PNE), nocturia or central diabetes insipidus. Also provided is a method of making a formulation by sublimating a solvent from a composition comprising desmopressin and a carrier material solution.

Description

  The present invention relates to pharmaceutical formulations, methods for their production and their use in the treatment and prevention of diseases in mammals, particularly humans.

  Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a vasopressin analog with high antidiuretic activity. It is marketed as the acetate salt in both tablets and nasal sprays and is generally prescribed for postponed excretion, incontinence, primary nocturnal urine (PNE) and nocturia, especially central diabetes insipidus.

  Existing desmopressin preparations meet patient needs, but there is still room for improvement. Tablets are often preferred by patients because they are easy to use, discretionary, and can be administered correctly. However, tablets generally need to be taken with water or other beverages in a cup, but desmopressin treatment is problematic because it requires limiting fluid intake, and the patient's intention is significantly clearer if no water is consumed become. Furthermore, the bioavailability of desmopressin when taken by tablet is about 0.1% compared to intravenous injection, and this figure clearly has room for improvement.

  Intranasal administration is highly bioavailable but is not preferred by patients. Furthermore, intranasal administration has an adverse effect on cilia, and viruses and bacteria tend to enter the mucous membrane.

  Sublingual preparations of desmopressin have been proposed so far. Grossman et al., Br. Med. J. et al. 1215 (17 May 1980) reports the administration of desmopressin by an unspecified sublingual lozenge. In the same year, Laczi et al., Int. J Clin. Pharm. Ther. Tox. 18 (12) 63-68 (1980) reports the administration of 30 μg desmopressin with 200 mg sublingual tablets containing sucrose, potato starch, stearin, ethanol (as purified spirit), clear gelatin, distilled water and powdered cocoa. . However, WO-A-8502119 states that: So-called sublingual tablets are also not preferred because they require a relatively long dissolution time and depend on the patient's salivation [WO-A-8502119, page 2]. , Lines 4-6].

  Fjellestad-Paulsen et al., Clin. Endocrinol. 38 177-82 (1993) administers a subnasal liquid nasal spray formulation of desmopressin to avoid the above problems of sublingual tablets. However, the authors report no detectable desmopressin in the blood after sublingual administration of liquid.

  It has now been discovered that desmopressin can be administered as a solid oral dispersible formulation that provides improved bioavailability compared to conventional oral tablets of desmopressin.

  According to a first aspect of the present invention, there is provided an oral dispersible pharmaceutical formulation of desmopressin.

  Desmopressin may be in the form of the free base, pharmaceutically or optionally a veterinarily acceptable salt, or any other pharmaceutically or veterinarily acceptable form. Acetate is particularly preferred.

  The formulation is generally solid. It can be rapidly dispersed in the oral cavity within 10, 5, 2 seconds, or within 1 second in ascending order of suitability. Such a preparation is called “oral dispersibility”. The formulations generally comprise a pharmaceutically acceptable (or veterinarily acceptable when administered to non-human animal) carrier suitable for this purpose.

  The daily dose of desmopressin measured as the free base is generally 0.5 or 1 μg to 1 mg / formulation. In one preferred dose range, the dose is generally 2 μg to 800 μg / formulation, with 10 μg to 600 μg being preferred. For example, relatively low doses of, for example, 0.5 μg to 75 μg are anticipated, with 0.5 or 1 μg to 50 μg being preferred. When administering one formulation per day, as is common with PNE and nocturia, this is the dose per formulation. If the daily dose is administered in two or more divided doses as is usual in the case of central diabetes insipidus, the amount of active compound per formulation is correspondingly reduced.

  Other active ingredients can be added whether or not they are peptides.

  The pharmaceutical preparation of the present invention is suitable for supplying the active ingredient to the oral cavity. The active ingredient can be absorbed through the sublingual mucosa and / or other routes (eg, through the buccal and / or gingival mucosa) from the oral cavity and / or from the gastrointestinal tract for systemic distribution.

  Various formulations are known that are suitable for delivering other active ingredients for absorption from the oral cavity. Such formulations may also be useful in the present invention. Among these, the active ingredient, the sugar containing lactose and / or maltose, and 0.12-1.2 w / w% agar based on the solid component, 400 mg / ml to 1,000 mg / ml Special mention is made of a buccal disintegrating solid formulation with sufficient density and sufficient handling strength, ie sufficient strength to withstand removal from blister packaging without actually disintegrating. Such a preparation and its production method are disclosed in US-A-5466464, and reference is made thereto for details.

  In one aspect of the invention, sugar can be used in the components in an amount of at least 50 w / w%, preferably 80 w / w% or more, more preferably 90 w / w% or more based on the total solid components. Depending on the quality and quantity of the active ingredient used, it may vary.

  Although the kind of agar is not specifically limited, It is preferable to use what is described in the Japanese pharmacopoeia. Examples of such agar include agar powder PS-7 and PS-8 (Ina Food Products).

  Agar can be used in an amount of 0.12-1.2 w / w%, preferably 0.2-0.4 w / w%, based on solid components.

  In order to produce the preparation according to this aspect of the present invention, a sugar containing lactose and / or mannitol is suspended in an agar aqueous solution, filled in a mold, solidified into a jelly form, and then dried. The concentration of the agar aqueous solution can be 0.3 to 2.0%, preferably 0.3 to 0.8%. The agar aqueous solution should be used in such an amount that the mixing ratio of the agar based on the solid component is 0.12 to 1.2 w / w%, preferably 40 to 60 w / w% of the agar solution based on the solid component. Can do.

  Other known formulations for delivering active ingredients for absorption from the oral cavity are those disclosed in US-A-6024981 and US-A-6221392. These formulations are hard compression fast-dissolving formulations suitable for direct oral administration, comprising an active ingredient and a matrix containing non-direct compression fillers and lubricants, which dissolve rapidly in the patient's oral cavity Is suitable for liberating the active ingredient. S. P. Having a friability of about 2% or less when tested in accordance with the invention, the formulation optionally has a hardness of at least about 15 Newtons (N), preferably 15-50N. US-A-6024981 and US-A-6221392 disclose further details and features of these formulations and methods for their production.

  The formulation according to this aspect of the invention preferably dissolves within about 90 seconds (preferably within 60 seconds, most preferably within 45 seconds) in the oral cavity of the patient. In many cases, it is also desirable for the formulation to contain at least one particle. The particles are an active ingredient and a protective agent. These particles include rapid release particles and / or sustained release particles.

  A particularly preferred formulation according to this aspect of the invention provides a hard compressed fast dissolving tablet suitable for direct oral administration. This tablet contains particles composed of an active ingredient and a protective agent. These particles are provided in an amount of about 0.01 to about 75% by weight based on the weight of the tablet. The tablet further comprises a non-direct compression filler, a wicking agent, and a hydrophobic lubricant. The tablet matrix includes at least about 60% rapidly water soluble components based on the total weight of the matrix material. The tablets have a hardness of about 15 to about 50 Newtons and a U.D. S. P. It has a friability of less than 2% when measured by the method, and is suitable for liberating the particles by spontaneous dissolution in the patient's mouth within about 60 seconds, and can be stored in bulk.

  Ultrafine or powdered sugars known as non-direct compression sugars can be used as fillers in the matrix of this aspect of the invention. Due to its chemical composition and its fine particle size, this material dissolves easily in the oral cavity within a few seconds when immersed in saliva. This not only means increasing the dissolution rate of the formulation, but also helps the filler feel a “gritty” feel while the patient holds the dissolving formulation in the mouth. It also means not. In contrast, a direct compression form of the same sugar is usually granulated and processed to be large and easy to compress. These sugars are water soluble but cannot be solubilized sufficiently quickly. As a result, it becomes easy to have a rough feel as the preparation dissolves. The dissolution time in the oral cavity can be measured by observing the dissolution time of the tablet in water at about 37 ° C. The tablets are immersed in water in the absence of forced stirring or with minimal stirring. The dissolution time is a time measured by visual observation from the time of immersion until the rapidly water-soluble component of the tablet is substantially completely dissolved.

  According to the invention, particularly preferred fillers are non-direct compression sugars and sugar alcohols meeting the above specifications. Such sugars and sugar alcohols include but are not limited to dextrose, mannitol, sorbitol, lactone and sucrose. It will be appreciated that, for example, dextrose can exist as a direct compressed sugar, ie a sugar that has been processed to increase its compressibility or a non-direct compressed sugar.

  In general, the remainder of the formulation can be a matrix. Thus, the percentage of filler can reach 100%. In general, however, the amount of non-direct compression filler useful according to the present invention is about 25 to about 95%, preferably about 50 to about 95%, more preferably about 60 to about 95%.

  The amount of lubricant used can generally be about 1 to about 2.5% by weight, more preferably about 1.5 to about 2% by weight. Hydrophobic lubricants useful in accordance with the present invention include alkali stearates, stearic acid, minerals and vegetable oils, glyceryl behenate and sodium stearyl fumarate. A hydrophilic lubricant can also be used.

  Protective agents useful according to this aspect of the invention include any polymer conventionally used in the formation of microparticles, matrix-shaped microparticles and microcapsules. Among these, cellulose materials such as natural cellulose and synthetic cellulose derivatives; acrylic polymers and vinyl polymers are exemplified. Other simple polymers include proteinaceous materials such as gelatin, polypeptides, and natural and synthetic shellacs and waxes. Protective polymers further include ethylcellulose, methylcellulose, carboxymethylcellulose and acrylic resin materials available under the trademark EUDRAGIT from Rhone Pharma GmbH, located in Weiterstadt, Germany.

  In addition to the above components, the matrix can further comprise a wicking agent, a non-foaming disintegrant and a foaming disintegrant. A wicking agent is a composition capable of sucking moisture into a formulation. The wicking agent facilitates moisture transport into the interior of the formulation. Thus, the formulation can be dissolved from inside and outside.

  Any compound that can function to transport moisture as described above can be considered a wicking agent. The wicking agent includes a number of conventional non-foaming disintegrants. Examples of these are, for example, microcrystalline cellulose (AVICEL PH 200, AVICEL PH 101), Ac-Di-Sol (croscarmellose sodium) and PVP-XL (cross-linked polyvinyl pyrrolidone); starches and modified starches, polymers, and gum arabic And gums such as xanthan gum. Compounds such as hydroxyalkyl cellulose such as hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, and carbopol can also be used.

  The conventional range of non-foaming disintegrants used in conventional tablets is as high as about 20%. In general, however, the amount of disintegrant used is about 2 to about 5% according to Handbook of Pharmaceutical Excipients.

  According to this aspect of the invention, the amount of wicking agent used can be 2 to about 12%, preferably 2 to about 5%.

  Of course, non-foaming disintegrants that cannot function to absorb moisture may be added if desired. In either case, it is preferred to use a rapid water-soluble non-foaming disintegrant or wicking agent and / or to minimize the use of a substantially water-insoluble wicking or non-foaming disintegrant. Non-rapid Dissolving Non-rapid water-soluble ingredients should be minimized as they can be used in substantial amounts, as they can degrade the feel of the tablet as it dissolves in the oral cavity. Of course, as described above, rapid water-soluble wicking agents or non-foaming disintegrants can be used in large amounts and do not promote formulation roughness during dissolution. Preferred wicking agents according to the invention include cross-linked PVP, but these are not rapidly water soluble and need to be reduced in amount.

  In addition, it may be desirable to use foam pairs in combination with other above components to improve the disintegration profile, tactile feel of the material, and the like. The foaming pair is preferably provided in an amount of about 0.5 to about 50%, more preferably 3 to about 15% by weight, based on the weight of the final tablet. It is particularly preferred to provide sufficient foamable material such that the gas generated when in contact with an aqueous environment is less than about 30 cm.

  The term “foam pair” refers to a compound that generates a gas. The preferred foam pair generates gas by a chemical reaction that occurs when the foamable collapse pair comes into contact with water and / or saliva in the oral cavity. This reaction is very often the result of the reaction of a soluble acid source with an alkali hydrogen carbonate or other carbonate source. The reaction of these two general compounds generates carbon dioxide gas when contacted with water or saliva. Such water activated materials must be maintained in a nearly anhydrous or stable hydrated form with little or no absorbed moisture because the tablets disintegrate prematurely upon contact with water. The acid source can be any safe for human consumption and generally includes food acids, acids and hydrite antacids, such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acid. Can be mentioned. Examples of the carbonic acid source include dry solid carbonates and bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, and magnesium carbonate. Reactants that generate oxygen or other gases and are safe for human consumption can also be added.

  In the case of an orally soluble tablet according to the present invention, a well-controlled amount of disintegrant, effervescent or non-effervescent or a combination thereof, so that the tablet provides a comfortable feel in the patient's mouth Is preferably provided. In some cases, the patient may have a rough and uncomfortable feeling as the tablet disintegrates in the oral cavity. In general, the total amount of wicking agent, non-foaming disintegrant and foaming disintegrant should be 0-50%. However, it should be noted that the formulation of the present invention dissolves rapidly, minimizing the need for disintegrants. As illustrated in the examples, suitable hardness, friability and dissolution time can be obtained without the use of foaming disintegrants or large amounts of wicking agents.

  The use of non-direct compression fillers eliminates the need for many conventional processing steps such as granulation and / or the need to purchase more expensive pre-granulated compressible fillers. At the same time, the resulting formulation is a balance between performance and stability. The formulation is sufficiently robust to be manufactured conventionally using direct compression. It is also robust enough for bulk storage or packaging. Moreover, it dissolves rapidly in the oral cavity while minimizing the discomfort of conventional disintegrating tablets.

The formulation according to this aspect of the invention comprises:
(A) forming a mixture comprising an active ingredient and a matrix comprising a non-direct compression filler and a lubricant;
(B) compressing the mixture to form a number of hard compression rapidly disintegrating formulations comprising active ingredients distributed in an orally soluble matrix; optionally (c) storing the formulation in bulk prior to packaging; It can manufacture by the method of including. In one preferred embodiment, the formulation is then packaged inside the package so that there is at least one per package. In a particularly preferred embodiment, the formulation is then packaged inside the package such that there are two or more per package. Direct compression is the preferred method of forming the formulation.

  Other known formulations for delivering active ingredients for absorption from the oral cavity are disclosed in US-A-6200604, as penetration enhancers to promote the buccal, sublingual and gingival mucosal penetration of pharmaceuticals. Contains orally administrable medicines together with the foaming agent used. In the context of the present invention, the medicament is desmopressin and in certain embodiments is administered through the sublingual mucosa. In the formulations of this aspect of the invention, the foaming agent may be used alone or in combination with other penetration enhancers to increase the oral absorption rate and extent of the active agent.

Formulations according to this aspect of the invention require the addition of an effective amount of foaming agent to promote oral mucosal penetration of the drug. The foaming agent is preferably added in an amount of about 5% to about 95% by weight based on the weight of the final tablet, more preferably about 30% to about 80% by weight. Tablet is greater than about 5 cm ³ upon contact with an aqueous environment, it is particularly preferred to add sufficient blowing agent to generate less gas than about 30 cm ^3.

  The term “foaming agent” refers to a compound that generates a gas. A preferred foaming agent generates gas by a chemical reaction that occurs when the foaming agent (foaming pair) comes into contact with water and / or saliva in the oral cavity. This reaction is very often the result of the reaction of a soluble acid source with a carbon dioxide source such as an alkali carbonate or bicarbonate. The reaction of these two general compounds generates carbon dioxide gas upon contact with water or saliva. Such water activated materials must be maintained in a nearly anhydrous or stable hydrated form with little or no absorbed moisture because the tablets disintegrate prematurely upon contact with water. The acid source can be any safe for human consumption and generally includes food acids, acids and hydrite antacids, such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acid. Can be mentioned. Examples of the carbonic acid source include dry solid carbonates and bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, and magnesium carbonate. Reactants that generate oxygen or other gases and are safe for human consumption can also be added.

  The blowing agent useful in this aspect of the invention need not necessarily participate in the reaction to form carbon dioxide. Reactants that generate oxygen and other gases that are safe for human consumption are also considered to be within this range. When the foaming agent contains two mutually reactive components such as an acid source and a carbonic acid source, it is preferable that both components react completely. Accordingly, equivalent ratio components that provide equal equivalents are preferred. For example, when the acid used is a diacid, it is necessary to use twice the amount of mono-reactive carbonate base or equivalent amount of di-reactive base so that it can be completely neutralized. However, in other aspects of the invention, the amount of acid or carbonate source may be greater than the amount of other components. This appears to be useful to increase the taste and / or performance of tablets containing either component in excess. In this case, the added amount of either component is allowed even if it remains unreacted.

  Such formulations can also contain a pH adjusting agent in addition to the materials necessary for foaming. For weakly acidic or weakly basic drugs, the pH of the aqueous environment may affect the relative ratio of the ionized and non-ionized forms of the drug present in solution according to the Henderson-Hasselback equation. The pH of the solution in which the foaming pair is dissolved becomes slightly acidic due to the generation of carbon dioxide. The pH of the local environment (e.g., saliva in direct contact with such drugs if the tablet and drug are dissolved from the tablet) can control the relative ratio of the ionized and non-ionized forms of the drug Can be adjusted by adding to the tablet. Thus, the formulation of the present invention can be optimized for each specific drug. If the non-ionized drug is known or expected to be absorbed through the cell mucosa (cell permeation absorption), the pH of the local environment (tolerable to the subject) to a level that favors the non-ionized form of the drug Preferably within a limited range). Conversely, if the ionized form is easily dissolved, the local environment should give priority to ionization.

  It is preferred that the aqueous solubility of the drug is not reduced by the foaming agent and the pH regulator so that the formulation can have a sufficient concentration of the drug present in the non-ionized form. Therefore, the percentage of pH modifier and / or blowing agent should be adjusted depending on the drug.

  Suitable pH adjusters for use in the present invention include any weak acid or weak base other than the materials necessary for foaming, or any buffer system that is harmless to the oral mucosa is preferred. Suitable pH modifiers for use in the present invention include, but are not limited to, any of the acids or bases mentioned above as foaming compounds, disodium hydrogen phosphate, sodium dihydrogen phosphate, and equivalent potassium salts.

  The formulations of this aspect of the invention preferably include one or more other ingredients to facilitate oral mucosal absorption of the pharmaceutical ingredients and improve the disintegration profile and tactile properties of the formulation. For example, the bioadhesive polymer can be added to the drug delivery system to improve the contact area between the formulation and the oral mucosa and the residence time of the formulation in the oral cavity. See, for example, Jonathan Eichman, Mechanical Studies on Infectious Permeability Enhancement (1997), incorporated herein by reference. Foaming also extends the residence time of the bioadhesive due to its mucosal detachability and prolongs the residence time of drug absorption. Examples of bioadhesives used in the present invention include, but are not limited to, Carbopol 934 P, Na CMC, Methocel, Polycarbophil (Noveon AA-1), HPMC, Na alginate, Na hyaluronate and other natural or synthetic organisms An adhesive is mentioned.

  In addition to the blowing agent, the formulation according to this aspect of the invention can further comprise a suitable non-foaming disintegrant. Examples of non-foaming disintegrants include, but are not limited to, microcrystalline cellulose, croscarmellose sodium, crospovidone, starch, corn starch, potato starch and its modified starches, sweeteners, clays (eg bentonite), alginates, gums (For example, guar gum, locust bean gum, karaya gum, pectin and tragacanth gum). The disintegrant can be up to about 20% by weight of the total weight of the composition, with about 2 to about 10% being preferred.

  According to this aspect of the invention, in addition to the particles, the formulation can also include glidants, lubricants, binders, sweeteners, aromas and coloring ingredients. Any conventional sweetener or fragrance component can be used. Sweeteners, fragrance ingredients, or combinations of sweeteners and fragrance ingredients can also be used.

  Examples of binders that can be used include gum acacia, gum tragacanth, gelatin, pectin, starch, cellulose materials (eg methylcellulose and sodium carboxymethylcellulose), alginic acid and its salts, magnesium magnesium silicate, polyethylene glycol, guar gum, polysaccharide acid, bentonite, Examples thereof include sugar and invert sugar. The binder can be used in an amount up to 60% by weight of the total composition, preferably from about 10 to about 40% by weight.

  Examples of the colorant include titanium dioxide and F.I. D. & C. Examples include pigments for food such as those known as pigments and natural colorants (eg grape skin extract, beet red powder, β-carotene, anato, carmine, turmeric, paprika, etc.). The amount of colorant used can be from about 0.1 to about 3.5% by weight of the total composition.

  The flavor added to the composition can be selected from synthetic aromatic oils and aromatic aromatics and / or natural oils, plant extracts, leaves, flowers, fruits and the like and combinations thereof. Examples of these include cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, eucalyptus oil, nutmeg oil, sage oil, bitter peach oil and sesame oil. Vanilla oil, citrus oil (such as lemon, orange, grape, lime and grapefruit) and fruit essence (such as apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc.) are also useful as flavors. Flavors found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavor depends on a number of factors such as the desired sensory effect. The flavor can be present in an amount of about 0.05 to about 3 weight percent based on the weight of the composition. Particularly preferred flavors are grape flavor, cherry flavor and citrus flavor (eg orange).

  One aspect of the present invention provides a solid oral tablet formulation suitable for sublingual administration. Excipient fillers can be used to facilitate tableting. The filler should also facilitate rapid dissolution of the formulation in the oral cavity. Examples of suitable fillers include but are not limited to mannitol, dextrose, lactose, sucrose, and calcium carbonate.

  Tablets can be manufactured by direct compression, wet granulation or any other tablet manufacturing technique as described in US-A-6200604. The formulation can be administered to a human or other mammalian subject by placing the formulation in the oral cavity of the subject and holding it sublingually in the oral cavity (sublingual administration). The formulation begins to disintegrate spontaneously due to moisture in the oral cavity. Disintegration and especially foaming further stimulates salivation and further disintegration.

  While the above formulation is within the scope of the present invention, the most preferred buccal dispersible solid pharmaceutical formulation according to the present invention comprises desmopressin and an open matrix network carrying desmopressin, the open matrix network being water-soluble that is inert to desmopressin. Alternatively, it is composed of a water dispersible carrier material.

  A pharmaceutical formulation comprising an open matrix network is known from GB-A-1548022, which is referred to for details. The pharmaceutical preparation of the present invention can be rapidly disintegrated with water. “Rapid disintegration” means that the molded product disintegrates within 10 seconds. The molded article is preferably disintegrated (dissolved or dispersed) within 5 seconds or even within 2 seconds or within 1 second or within a shorter time. Disintegration time was measured by Disintegration Test for Tables, B.E. P. Measured by a method similar to 1973. This method is described in GB-A-1548022 and is summarized below.

Apparatus No. 2 is formed so that a basket is formed at the lower end of glass or a suitable plastic tube having a length of 80 to 100 mm, an inner diameter of about 28 mm and an outer diameter of 30 to 31 mm. 1. Install a rust-proof fine wire mesh disk that meets the requirements of 1.70 sheaves.

  Water having a temperature of 36 to 38 ° C. is placed in a flat bottom glass cylinder having an inner diameter of about 45 mm to a depth of 15 cm or less.

  The basket is hung in the center of the cylinder so that the wire mesh can be washed away from the water at the highest position and the upper edge of the basket can be moved up and down uniformly so as not to be immersed in water.

Method Place one molded article in a basket and move it up and down to repeat the complete up and down motion at an equivalent rate of 30 times per minute. If the particles do not remain on the wire mesh that is difficult to pass the particles, the molded product is collapsed. It is desirable that no such particles remain after 10 seconds.

  As used herein, the term “open matrix network” refers to a water-soluble or water-dispersible carrier material with interspersed pores. The open matrix network of carrier material is generally low density. For example, the density can be in the range of 10-200 mg / cc, for example 10-100 mg / cc, preferably 30-60 mg / cc. The density of the molded article varies depending on the amount of the active ingredient and other optional components added to the molded article, and may be outside the preferred range described above for the density of the matrix network. An open matrix network that is similar in structure to a solid foam can allow liquid to enter the formulation through the gap and penetrate into it. Due to the penetration of the aqueous medium, the carrier material on both the inside and outside of the formulation is affected by the aqueous medium, and the network of carrier materials rapidly collapses. The open matrix structure is porous and facilitates the disintegration of the formulation compared to conventional solid molded pharmaceutical formulations such as tablets, pills, capsules, suppositories and pessaries. As a result of the rapid disintegration, the active ingredient carried by the matrix is rapidly released.

  The carrier material used in the formulations of the present invention is any water soluble or water dispersible material that is pharmacologically acceptable or drug inert and capable of forming an open matrix network that is rapidly disintegratable. It can be. Use of a water soluble material as a carrier is preferred because it results in the fastest disintegration of the matrix when the formulation is placed in an aqueous medium. Particularly advantageous carriers can be formed from polypeptides such as gelatin, in particular gelatin which has been hydrolyzed, for example by heating water. For example, gelatin can be partially hydrolyzed by heating an aqueous gelatin solution, for example, in an autoclave at about 120 ° C. for up to 2 hours, for example from about 5 minutes to about 1 hour, preferably from about 30 minutes to about 1 hour. Hydrolyzed gelatin is preferably used at a concentration of about 1-6% or 8% w / v, most preferably 2-4%, for example about 3%, or 4-6%, for example about 5%. As is clear from the examples below, these concentrations are for example the concentration of the entire preparation before dehydration by lyophilization.

  Mammal-derived gelatin may be used, but it has a poor taste, so in addition to the sweetener and flavor necessary to conceal the taste of the active ingredient, the use of sweetener and flavor is necessary to conceal the taste of gelatin become. In addition, the heating step required with the use of mammalian gelatin increases processing time and adds heating costs, thus increasing the overall cost of the process. Accordingly, fish gelatin, particularly non-gelling fish gelatin, is particularly preferred for desmopressin. See WO-A-0061117 for details.

  Other carrier materials may be used in place of the partially hydrolyzed gelatin or fish gelatin, such as hydrolyzed dextran, dextrin and other polysaccharides and alginate (eg sodium alginate) or the above carrier mutual or other carrier materials (eg polyvinyl A mixture of alcohol, polyvinylpyrrolidone or gum arabic) can be used. Instead of gelatin, modified starch as described in WO-A-0044351 may be used, see the same for details.

  Other carrier materials that can be used in addition to or in place of the above carriers include gums such as tragacanth, xanthan, carrageenan, and guar; mucus such as flaxseed mucus and agar; pectin and starch and derivatives thereof; In particular, polysaccharides and other carbohydrates such as soluble starches and dextrates; water-soluble cellulose derivatives such as hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and hydroxypropylcellulose; and carbomers.

  Fillers can also be added. It is also desirable that the filler facilitates rapid dissolution or dispersion of the formulation in the oral cavity. Examples of suitable fillers include, but are not limited to sugars such as mannitol, dextrose, lactose, sucrose, and sorbitol. The filler is preferably used at a concentration of about 0-6% or 8% weight / volume%, most preferably 2-4%, for example about 3%, or 4-6%, for example about 5%. Again, these concentrations are, for example, the concentration of the entire preparation before dehydration by lyophilization.

  The pharmaceutical preparation of the present invention can be in the form of a molded article. The formulation can contain ingredients other than the active ingredient. For example, the pharmaceutical formulation of the present invention can include a pharmaceutically acceptable adjuvant. Examples of such an adjuvant include coloring agents, fragrances, preservatives (for example, bacteriostatic agents) and the like. US-A-5188825 teaches that a water-soluble active agent should be combined with an ion exchange resin to form a substantially water-insoluble active agent / resin complex, which teaching is practiced in the present invention. However, the development of the present invention has shown that water-soluble peptides such as desmopressin can be formulated into the solid formulations of the present invention without the need to bind to ion exchange resins, for details (see US-A-5188825 for details). . Therefore, such a formulation does not require the addition of an ion exchange resin. Unlike desmopressin, for hydrophobic peptides, surfactants may be added as taught in US-A-5827541, see the same reference for details. For bad taste peptides (but not desmopressin), lipids such as lecithin can be added for patient acceptance as taught in US-A-6156339, see the same reference for details. I want to be. Other strategies for hiding taste include converting soluble salts to low soluble salts or free bases as taught in US-A-5738875 and US-A-5837287, or disclosed in US-A-59776577. Cooling suspensions of coarse particles of pharmaceutically active substance with or without a coating in a carrier material prior to lyophilization using a known method to reduce viscosity and minimize active substance release during processing In addition, the bad taste of the peptide can be minimized after the disintegration point of the oral preparation is exceeded (see the cited patent for details).

  In the case of large particle size insoluble or low soluble peptides, add xanthan gum which can function as a gelatin flocculant, especially when the carrier is formed from gelatin, as disclosed in US Pat. See the same document for details.

  As taught in WO-A-9323017, one or more having about 2 to 12 carbon atoms when the matrix is selected from the group consisting of gelatin, pectin, soy fiber protein and mixtures thereof The amino acid may be added. In this formulation, the preferred amino acid is glycine, the preferred matrix forming agent is gelatin and / or pectin, and in a particularly preferred embodiment the formulation further comprises mannitol.

  All excipients are selected to be pharmaceutically acceptable.

  The pharmaceutical formulation of the present invention can be manufactured by the method described in GB-A-1548022, the method comprising sublimating a solvent from a composition comprising a solution of a pharmaceutical substance and a carrier material in a solvent, The composition is in a solid state in the mold.

  Sublimation is preferably carried out by lyophilizing a composition comprising a solution of the active ingredient and carrier material in a solvent. The composition can include additional components as described above. The solvent is preferably water, but an auxiliary solvent (for example, an alcohol such as tert-butyl alcohol) may be added to improve the solubility of the drug. The composition can further comprise a surfactant, such as Tween 80 (polyoxyethylene (20) sorbitan monooleate). Surfactants can help prevent lyophilizates from sticking to the mold surface. It can also help disperse the active ingredient.

  The composition is used to adjust the pH of the solution before manufacturing the formulation to within the range of 3-6, preferably 3.5-5.5, most preferably 4-5, such as 4.5 or 4.8. A pH regulator may be included. Citric acid is a preferred pH adjusting agent, but hydrochloric acid, malic acid and the like can also be used. Such non-volatile pH modifiers can be present in the final formulation because they are not removed by lyophilization or other sublimation processes.

  The mold can include a series of cylindrical or other shaped recesses each sized to correspond to the desired size of the molded article. Alternatively, the size of the concave portion of the mold may be made larger than the desired size of the product, and the product may be cut into the desired size after freeze-drying the contents (for example, a thin wafer).

  However, as described in GB-A-2111423, the mold is preferably a recess in the film material sheet. The film material can include two or more recesses. The film material may be similar to that used in conventional blister packs used for packaging oral contraceptive tablets and similar pharmaceutical forms. For example, the film material can be made from a thermoplastic material having recesses formed by thermoforming. A preferred film material is a polyvinyl chloride film. A laminate of film material can also be used.

  In one aspect, the mold includes a metal plate (eg, an aluminum plate) that includes one or more recesses. In a preferred method of using such a mold, the mold is cooled with a refrigerant (eg, liquid nitrogen or solid carbon dioxide). Once the mold is cooled, the carrier material, active ingredient and other optional ingredients are added to a predetermined amount of water and fed into the recess. Once the contents of the recess are frozen, the mold is depressurized and heated under control if desired to promote sublimation. The pressure can be less than about 4 mm Hg, and GB-A-1548022 teaches that it is preferable to use a pressure of less than 0.3 mm Hg, such as 0.1-0.2 mm. The lyophilized product can then be removed from the mold recess and stored in a hermetic jar or other suitable storage container for future use. Alternatively, the freeze-dried product may be wrapped in a film material as described in GB-A-2111423.

  GB-A-2111423 is described in GB-A-2111423 as a method developed thereafter, which is useful for the production of the pharmaceutical preparation according to the present invention. The method includes filling a mold with a composition comprising a predetermined amount of an active ingredient and a partially hydrolyzed gelatin solution, and freezing the composition in the mold by passing a gas refrigerant over the mold. Then sublimating the solvent from the frozen composition to form a network of partially hydrolyzed gelatin carrying the active ingredient.

  In order to easily ensure a uniform thickness of the product, one or more side walls of the mold are spread from the bottom to the outside as described in GB-A-2119246, and the angle of the normal to the surface of the composition is increased. It can be at least 5 °, see the same document for details.

  In lieu of or in addition to the above, the pharmaceutical formulation of the present invention can be manufactured by a method as described in GB-A-2114440, which is water-soluble or water-dispersible inert to the active ingredient Freezing a composition comprising a solution of a functional carrier material in a first solvent, sublimating the first solvent from the frozen composition to produce a product having a network of carrier materials, a predetermined amount of Adding a solution or suspension of a second non-aqueous solvent containing the active ingredient to the product and evaporating the second solvent. For details, refer to GB-A-2114440.

  In lieu of or in addition to the above, the pharmaceutical formulation of the present invention can be manufactured by a method as described in GB-A-2111184, which is maintained at a temperature lower than the freezing point of the liquid medium, A liquid medium in the form of droplets is introduced below the surface of the cooling liquid that is immiscible and inert to the liquid medium and is denser than both the liquid medium and the resulting frozen particles, and the liquid droplets are Freezes as it floats toward its surface, forming spherical particles. Frozen spherical particles can be collected at or near the top surface of the coolant. Refer to GB-A-2111184 for details.

  The preparation according to the invention has improved bioavailability. The formulation is intended for oral administration and is very suitable for this purpose. The formulation disperses rapidly in the oral cavity and may be inserted, for example, sublingually (sublingually) or attached to the tongue or on the cheek or gum.

  According to a second aspect of the present invention, there is provided a formulation as described above for use in particular for postponement of excretion or incontinence, primary nocturnal urine (PNE), nocturnal polyuria and central diabetes insipidus.

  The present invention provides a method of delaying excretion and treating or preventing incontinence, primary nocturnal urine (PNE), nocturnal polyuria and / or central diabetes insipidus, which generally comprises a non-toxic effective amount of desmopressin. Orally dispersible pharmaceutical preparations such as the above preparations. Any other disease or condition treatable or preventable by desmopressin can be treated according to the invention as well. The invention therefore also relates to the use of desmopressin in the manufacture of an orally dispersible pharmaceutical formulation. The invention further relates to a pack comprising desmopressin orally dispersible pharmaceutical formulation and instructions describing how to administer the formulation to the oral cavity of a patient. A method of producing a desmopressin packaged formulation is also included in the present invention, which includes enclosing instructions describing the oral dispersible pharmaceutical formulation of desmopressin and the method of administering the formulation to the oral cavity of the patient. The instructions may be printed, for example, on a packaging containing the formulation at the time of sale or distribution, or may be described in a product information booklet or an attachment within the packaging.

  Peptides other than desmopressin can also be formulated into the above formulation. Accordingly, the present invention also relates to an orally dispersible pharmaceutical formulation of a pharmaceutically active peptide.

  According to another aspect of the invention, a pharmaceutically active peptide and an open matrix network carrying the peptide, the open matrix network being composed of a water soluble or water dispersible carrier material that is inert to the peptide. A solid pharmaceutical formulation is provided.

  Oral vaccines made from rapidly dissolving formulations are known from WO-A-9921579, but no pharmaceutically active peptide is disclosed which maintains its activity after administration. The experimental results in WO-A-9921579 only show that IgA antibodies against tetanus toxoid are present in saliva after administration of tetanus toxoid with an adjuvanted fast dissolving vaccine formulation. The formulation of the present invention is not a vaccine and does not contain an adjuvant.

  The pharmaceutical formulation of this aspect of the invention comprises a pharmaceutically active peptide. Such peptides may themselves be directly active or may have one or more active metabolites, i.e., prodrugs of primary or true active ingredients. Peptides can have, for example, 2-20, preferably 5-15 amino acid residues (the L-isomer is generally predominant, but at least a portion may be the D-isomer). Peptides can be linear, branched or cyclic and can contain natural residues or substituents or residues or substituents that are generally or not present in natural peptides or proteins. Where necessary, pharmaceutically acceptable salts, simple adducts and tautomers are also included.

Examples of peptides usefully formulated in accordance with the present invention include somatostatin and analogs thereof (eg, cyclo (MeAla-Tyr-D-Trp-Lys-Val-Phe) and cyclo (Asn-Phe-Phe-D-Trp-). Lys-Thr-Phe-GABA)), enkephalins (eg Met ⁵ -enkephalin and Leu ⁵ -enkephalin), oxytocin analogues (eg atociban (1-deamino-2-D-Tyr- (OEt) -4-Thr-8) -Orn- oxytocin)), GnRH analogs (e.g. triptorelin (6-D-Trp-GnRH ), leuprolide ^{([D-Leu 6, Pro} 8 -NHEt] -GnRH), degarelix (Ac-D-2Nal-D- 4Cpa-D-3Pal-Ser-4Aph (L-hydroorotic ) -D-4Aph (Cbm) -Leu -Ilys-Pro-D-Ala-NH 2) ( wherein, 2Nal 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is 3-pyridylalanine, ILys is N (Ε) -isopropyllysine, 4Aph is 4-aminophenylalanine, and Cbm is a carbamoyl group)) and other GnRH antagonists disclosed in US-A-5925730 and US-A-4072668, and vasopressin analogs ( For example, desmopressin). Since agonists can be active at lower doses than antagonists, it is particularly preferred to formulate agonists of naturally active peptides such as those described above according to the present invention.

  The dose will be determined by the attending physician or clinician depending on the type of peptide, the type of disease or disorder to be treated or prevented, and other factors.

  The invention also relates to the use of a peptide in the manufacture of a formulation as described above for treating or preventing a disease or disorder treatable or preventable by the peptide.

  The invention further provides a method of treating a disease or disorder treatable or preventable by a peptide, the method generally comprising administering to the subject a non-toxic effective amount of the peptide as a formulation as described above.

  The contents of each reference cited herein are incorporated herein by reference to the maximum legally permitted extent.

  Preferred features of each aspect of the invention and, where feasible and necessary, each embodiment of each aspect of the invention applies to other aspects or embodiments as appropriate. In particular, the above aspects, features and embodiments of the present invention relating to demopressin shall be applicable to other peptides.

  The following examples illustrate the invention.

200 μg Desmopressin Oral Dispersible Formulation Spray dried fish gelatin (4 g) and mannitol (3 g) are added to a glass beaker. Purified water (93 g) is then added and dissolved by stirring using a magnetic follower. Check pH and adjust to 4.8 with citric acid if necessary.

  The Gilson pipette can then be used to dispense 500 mg of this solution into each of a series of preformed blister pockets having a pocket diameter of about 16 mm. The blister laminate can be composed of PVC coated with PVdC. Next, each metering unit was frozen at a temperature of −110 ° C. in a freezing tunnel with a residence time of 3.2 minutes, and each frozen unit was then cooled to a temperature of −25 ° C. (± 5 ° C. for 1.5 hours or longer in a vertical freezer ). The units are then lyophilized overnight at an initial shelf temperature of 10 ° C. to + 20 ° C. under a pressure of 0.5 mbar. Each unit can be checked for moisture before removal by dry tracing and pressurized moisture check.

Thus, according to the general procedure described in Example 1 of WO-A-0061117, a desmopressin oral dispersible formulation is prepared using the following ingredients per unit formulation.
Desmopressin (PolyPeptide Laboratories, Sweden)
200 μg
Mannitol EP / USP (Roquette, Mannitol 35) 15mg
Fish gelatin USNF / EP 20mg
Citric acid (if necessary) [pH adjuster] Purified water up to pH 4.8 [removed during processing].

400 μg desmopressin oral dispersible formulation The procedure of Example 1 of the present invention is followed except that the amount of desmopressin per unit formulation is 400 μg.

800 μg desmopressin oral dispersible formulation The procedure of Example 1 of the present invention is followed except that the amount of desmopressin per unit formulation is 800 μg.

200 [mu] g Desmopressin Oral Dispersible Formulation According to the general procedure described in Example 1 of WO-A-0061117, a desmopressin oral dispersible formulation was prepared using the following ingredients per unit formulation.
Desmopressin (PolyPeptide Laboratories, Sweden)
200 μg
Mannitol EP / USP (Roquette, Mannitol 35) 6mg
Fish gelatin USNF / EP 10mg
Citric acid (if necessary) [pH adjuster] Purified water up to pH 4.8 [removed during processing].

400 μg desmopressin buccal dispersible formulation The procedure of Example 4 of the present invention was followed except that the amount of desmopressin per unit formulation was 400 μg.

800 μg desmopressin oral dispersible formulation The procedure of Example 4 of the present invention was followed except that the amount of desmopressin per unit formulation was 800 μg.

(Comparative Example 1)
Desmopressin i. v. Solution An injectable formulation of desmopressin was prepared in a conventional manner using the following ingredients.
Desmopressin (PolyPeptide Laboratories, Sweden)
4mg
Sodium chloride (National Corporation of Swedish Pharmacies, Sweden) 9mg
Hydrochloric acid (1N) (Merck, Germany) Appropriate amount up to pH 4 Appropriate amount up to 1 ml of water for injection.

(Comparative Example 2)
200 μg desmopressin conventional tablets Tablets containing the following ingredients were prepared using a conventional wet granulation method.
Desmopressin (PolyPeptide Laboratories, Sweden)
200 μg
Lactose (Pharmacatose 150M, DMV, Netherlands) 120mg
Potato starch (Lickeby AB, Sweden) 77mg
PVP (Kollidon 25, BASF, Germany) 1.8mg
Magnesium stearate (Peter Greven, Germany) 1mg
Granulation liquid (water, ethanol) [removed during processing].

(Comparative Example 3)
100 μg desmopressin conventional tablets The procedure of Comparative Example 2 was followed except that the amount of desmopressin was 100 μg / tablet.

Bioavailability of desmopressin administered according to Examples 4-6 Test design This study was conducted on 24 healthy non-smoking male volunteers. The study was designed as a one-center, open-label, randomized, balanced, 4-group crossover phase I study. 200 μg, 400 μg and 800 μg oral dispersible formulations (Examples 4, 5 and 6 respectively) and i. v. As a bolus (Comparative Example 1), 2 μg of desmopressin was administered sublingually to each subject in random order. There was a 72-hour withdrawal period between doses. In order to standardize the buccal mucosa prior to the administration of the orally dispersible tablets, subjects were asked not to eat food, gum, etc. Subjects were asked to brush their teeth without applying toothpaste before morning administration.

Blood samples Blood samples for plasma desmopressin concentration were collected according to the following schedule: 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, before dosing, After 8 hours, 10 hours, 12 hours and 24 hours. After intravenous administration, blood samples were collected at 5 minutes and 10 minutes after dosing.

Assay Desmopressin concentration in plasma was measured by an approved RIA method.

Pharmacokinetic analysis Commercial software WinNonlin® Pro, ver. The desmopressin concentration in plasma was analyzed for individual volunteers in each treatment group by non-compartmental method using 3.2 (Pharsight Corporation, USA). If a value above the LOQ was detected after a plasma concentration value below the limit of quantification (LOQ), it was set to “LOQ / 2” by NCA analysis and descriptive statistics for the concentration. If no value above LOQ was detected after the value below LOQ, it was excluded from the NCA analysis and set to zero for concentration descriptive statistics.

Results of pharmacokinetic analysis i. v. The steady state mean volume of distribution (Vss) after administration was 29.7 dm ³ . When the average clearance was calculated, it was 8.5 dm ³ / hour, and the average elimination half-life was found to be 2.8 hours. After oral administration of desmopressin, the highest plasma concentration was observed 0.5-2.0 hours after dosing. The maximum plasma concentrations were 14.25, 30.21 and 65.25 pg / ml after oral administration of 200, 400 and 800 μg, respectively. After reaching the maximum, desmopressin was excreted with an average elimination half-life of 2.8-3.0 hours. The bioavailability was found to be 0.30% with a 95% confidence interval of 0.23 to 0.38%.

  The pharmacokinetics of desmopressin is linear when administered as an oral dispersible formulation of Example 4, 5 or 6.

(Comparative Example 4)
Bioavailability of desmopressin administered according to Comparative Examples 2 and 3 This study was designed as an open-label, single-dose, 3-group crossover study and targeted 36 healthy male volunteers (white, black and Hispanic). 200 μg tablets (Comparative Example 2) 200 μg of desmopressin as one tablet, 200 μg of desmopressin as 100 tablets (Comparative Example 3) and i. v. As a bolus administration (Comparative Example 1), 2 μg was administered to each subject in random order.

  i. v. The mean elimination half-life after administration was found to be 2.24 hours. After oral administration of desmopressin, the highest plasma concentration was observed 1.06 hours (2 × 100 μg) or 1.05 hours (1 × 200 μg) after dosing. Maximum plasma concentrations were 13.2 and 15.0 pg / ml after oral administration of 2 × 100 μg and 1 × 200 μg, respectively. The bioavailability was found to be 0.13% (2 × 100 μg) or 0.16% (1 × 200 μg).

Claims (27)

  An oral dispersible pharmaceutical preparation of desmopressin.   The preparation according to claim 1, which is an oral dispersible solid pharmaceutical preparation.   A solid pharmaceutical formulation comprising desmopressin and an open matrix network carrying desmopressin, wherein the open matrix network is composed of a water soluble or water dispersible carrier material inert to desmopressin.   The formulation of claim 3, wherein the open matrix network comprises gelatin.   The preparation according to claim 4, wherein the gelatin is fish gelatin.   The preparation according to claim 5, wherein the fish gelatin is non-gelling.   A method of producing a solid pharmaceutical formulation comprising subliming a solvent from a composition comprising a solution of desmopressin and a carrier material in a solvent, wherein the composition is in a solid state in a mold.   8. The method of claim 7, wherein sublimation is performed by lyophilizing a composition comprising a solution of desmopressin and a carrier material in a solvent.   The method according to claim 7 or 8, wherein the solvent is water.   10. A method according to claim 7, 8 or 9, wherein the pH of the solution is 3-6, preferably 3.5-5.5, most preferably 4-5.   The preparation according to any one of claims 1 to 10, for use in medicine.   The preparation according to any one of claims 1 to 10, for postponement of excretion, or for treatment or prevention of incontinence, primary nocturnal urine (PNE), nocturnal polyuria or central diabetes insipidus.   Use of desmopressin in the manufacture of an orally dispersible pharmaceutical formulation.   A method of treating or preventing a disease or disorder treatable or preventable by desmopressin, said method comprising administering to a subject a generally non-toxic effective amount of desmopressin as an orally dispersible pharmaceutical formulation.   15. The method according to claim 14, which is a method for postponing excretion, or a method for treating or preventing incontinence, primary nocturnal urine (PNE), nocturnal polyuria and / or central diabetes insipidus.   A pack containing instructions describing how to administer the desmopressin orally dispersible pharmaceutical formulation and the formulation to the oral cavity of the patient.   A method for producing a packaged preparation of desmopressin, comprising: bundling instructions describing how to administer the dispersible pharmaceutical preparation of desmopressin to the oral cavity of a patient and the oral cavity of a patient.   An orally dispersible pharmaceutical preparation of a pharmaceutically active peptide.   The preparation according to claim 18, which is an oral dispersible solid pharmaceutical preparation.   A solid pharmaceutical formulation comprising a pharmaceutically active peptide and an open matrix network carrying the peptide, wherein the open matrix network is composed of a water-soluble or water-dispersible carrier material that is inert to the peptide.   21. The formulation according to any one of claims 18 to 20, wherein the peptide is somatostatin or an analog thereof, enkephalin, oxytocin analog, LH-RH analog, GnRH analog or vasopressin analog.   21. The formulation of claim 20, wherein the open matrix network comprises gelatin.   The formulation according to claim 22, wherein the gelatin is fish gelatin.   24. The formulation of claim 23, wherein the fish gelatin is non-gelling.   A method for producing a solid pharmaceutical formulation comprising a pharmaceutically active peptide comprising sublimating a solvent from a composition comprising a peptide and a solution of a carrier material in a solvent, wherein the composition is in a solid state in a mold. Said method.   26. The method of claim 25, wherein sublimation is performed by lyophilizing a composition comprising a peptide and a solution of a carrier material in a solvent.   25. A formulation according to any one of claims 18 to 24 for pharmaceutical use.