HRP20041152A2 - Pharmaceutical formulations - Google Patents

Description

This invention relates to pharmaceutical formulations, methods of their preparation and their use in the treatment and prevention of diseases in mammals, especially humans.

Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is a vasopressin analog that has a high antidiuretic effect. It is commercially available as the acetate salt in tablet form and as a nasal spray, and is commonly prescribed for urinary incontinence, incontinence, primary nocturnal enuresis (PNE), and nocturnal enuresis, among other indications, including central diabetes insipidus.

While existing formulations of desmopressin have responded to patient needs, there is still a need for improvement. Patients usually prefer tablets because of their ease of use, discretion and lack of uncertainty in correct administration. However, the tablets usually need to be taken with a glass of water or other drink, which is a problem when fluid intake needs to be restricted during desmopressin treatment, and the message to the patient is much clearer when no fluid is taken at all. Furthermore, the bioavailability of desmopressin taken in a tablet is 0.1%, which, compared to intravenous injection, is a figure that obviously leaves room for improvement.

Administration through the nose (intranasal administration) provides greater bioavailability, but is less desirable in patients. Furthermore, intranasal administration can have a bad effect on the cilia, so that viruses and bacteria can more easily pass into the mucous membrane.

Sublingual formulations of desmopressin have been proposed previously. Grossman et al., Br. Honey. J. 1215 (May 17, 1980) report on the use of desmopressin in sublingual lozenges of undefined composition. In the same year, Laczi et al., Int. J. Clin. Pharm. Ther. Tox. 18 (12) 63-68 (1980) report the use of 30 μg desmopressin in a 200 mg sublingual tablet containing sucrose, potato starch, stearin, ethanol (from distilled spirit), white gelatin, distilled water, and cocoa powder. However, in WO-A-8502119 it is written:

The so-called sublingual tablet is undesirable considering that

requires a relatively long dissolution time and its dependence on

the patient's saliva secretion. [WO-A-8502119, page 2, line 4-6]

Fjellestad-Paulsen et al., Clin. Endocrinol. 38 177-82 (1993) applied a sublingual liquid nasal spray formulation of desmopressin, which avoided the aforementioned problems associated with the sublingual tablet. However, the authors reported that, when the liquid was administered sublingually, no traces of desmopressin were found in the blood.

It has been discovered that desmopressin can be administered as a solid orodispersible dosage form which provides improved bioavailability compared to conventional oral desmopressin tablets.

According to a first aspect of the invention, an orodispersible pharmaceutical dosage of desmopressin is provided.

Desmopressin may be in the form of a free base or a pharmaceutically or, where appropriate, a veterinary acceptable salt, or in any pharmaceutically or veterinary acceptable form. The acetate salt is particularly preferred.

As a rule, the formulation will be rigid. It can be rapidly dispersed in the mouth, for example within 10, 5, 2 seconds, or even within 1 second, in increasing order of desirability. Such formulations are called orodispersible. As a rule, the formulation will contain carriers suitable for this purpose, which will be pharmaceutically acceptable (or veterinary acceptable in the case of application to animals).

The daily dose of desmopressin, measured as free base, will generally be from 0.5 or 1 μg to 1 mg per dosage. In the preferred dosage range, the dosage will typically range from 2 μg to 800 μg per dosage and preferably from 10 g to 600 μg. Particularly contemplated are relatively low doses, for example from 0.5 μg to 75 μg, preferably 0.5 or 1 μg to 50 μg. When a single dose per day is administered, as is common with PNE and nocturnal enuresis, this will be a typical dosing regimen. When two or more doses per day are administered, as is usual in the case of central diabetes insipidus, the amount of active ingredient per dose will be correspondingly reduced.

Other active ingredients, whether peptides or not, may also be present.

The pharmaceutical dosages of the present invention are adapted to supply the oral cavity with the active substance. The active substance can be absorbed through the sublingual mucosa, and/or otherwise via the oral cavity. (ie through the mucous membrane of the mouth and/or gums) and/or through the gastrointestinal tract for systematic distribution.

A variety of formulations are known which are suitable for supplying other active ingredients for absorption through the oral cavity. Such formulations may be useful for the subject invention. Among them are orally degradable solid formulations or preparations containing an active ingredient, a sugar containing lactose and/or mannitol and a weight percentage of 0.12 to 1.2, based on solid components, of agar and having a density of 400 mg/ml to 1,000 mg /ml and has sufficient strength for manipulation, which in practice may mean sufficient strength to withstand removal from the blister pack without degradation. Such formulations, and how to make them, are described in US-A-5466464, to which reference is made hereinafter.

In this embodiment of the invention, sugar can be used in the formulation in an amount of at least 50 percent by weight, preferably 80 percent by weight, more preferably 90 percent by weight or more, based on total solids, although it may vary depending on the quality and quantity of the active ingredient. which will be used.

Although the types of agar are not particularly limited, it is preferable to use those listed in the Japanese Pharmacopedia. Examples of said agars include PS-7 and PS-8 agar powders (manufactured by Ina Shokuhin).

Agar can be used in an amount of 0.12 to 1.2 percent by mass, preferably up to 0.2 to 0.4 percent by mass, based on the weight of the solid components.

In order to produce formulations in accordance with an embodiment of the present invention, a sugar containing lactose and/or mannitol is dissolved in an aqueous agar solution, filled into a mold, solidified into a gelatinous form, and then dried. Aqueous agar solution can have a concentration of 0.3 to 2.0%, preferably from 0.3 to 0.8%. The aqueous agar solution can be used in such an amount that the ratio of agar based on solid components becomes 0.12 to 1.2 percent by mass, but preferably 40 to 60 percent by mass of the agar solution based on solid components.

Other formulations known to deliver the active ingredients for absorption from the oral cavity are the dosages contained in US-A-6024981 and US-A-6221392. These are hard, compressed, fast-dissolving dosages adapted for direct oral dosing, which contain: an active ingredient and a matrix including an indirect pressure filler and a lubricant, said dosage adapted for rapid dissolution in the patient's mouth and thus releases said active ingredient, and has a thickness of approx. 2% or less when tested according to U.S.P. (United States Pharmacopeia), said dosage preferably having a hardness of at least 15 Newtons (N), preferably 15-50 N. US-A-6024981 and US-A-6221392 describe further details and characteristics of these dosages and how to make.

Preferably, the dosage according to this embodiment of the invention dissolves in about 90 seconds or less (preferably 60 seconds or less, most preferably 45 seconds or less) in the patient's mouth. It is also often desirable that the dosage contains at least one particle. The particle would be the active ingredient and protective material. These particles may contain fast-release particles and or sustained-release particles.

In a particularly preferred formulation in accordance with this embodiment of the present invention, a hard, compressed, rapidly dissolving tablet adapted for direct oral dosing is provided. The tablet contains particles made of the active ingredient and a protective material. These particles can be found in an amount between about 0.01 and about 75% based on the weight of the tablet. The tablet also contains a matrix constructed from an indirectly pressed filler, an absorption aid, and a hydrophobic lubricant. The tablet matrix contains at least about 60% water-soluble ingredients based on the total weight of the matrix material. The tablet has a hardness between about 15 and about 50 Newtons, and a friability of less than 2% when measured by U.S.P. and it is adapted to dissolve spontaneously in the patient's mouth in less than about 60 seconds, thus releasing the aforementioned particles and being able to be stored in bulk.

Very finely granulated or powdered sugar known as indirect pressed sugar can be used as a filler in the matrix of this embodiment of the present invention. This material, partly because of its chemical composition and partly because of its fine particle size, will dissolve immediately in the mouth, within seconds of being moistened with saliva. Not only does this mean that it can contribute to the rate at which the dosage will dissolve, but it also means that while the patient is holding the dissolving dosage in the mouth, the filler will not contribute to a "grainy" or "gritty" texture that adversely affects the organoleptic sensation of taking the dosage. In contrast, direct pressed versions of the same sugar are usually granulated and treated to make them larger and easier to compress. While these sugars are soluble in water, they do not need to be dissolved quickly enough. As a result, they can contribute to a ʺgrainyʺ or ʺgrittyʺ' texture of the dosage as it dissolves. The dissolution time in the mouth can be measured by observing the dissolution time of the tablet in water at about 37°C. The tablet is immersed in water without vigorous stirring or with minimal stirring. Dissolution time is the time from immersion to complete dissolution in water of the fast-dissolving ingredients of the tablet as determined by visual observation.

Particularly preferred fillers, in accordance with the present invention, are indirectly compressed sugars and sugar alcohols that correspond to the specifications discussed above. Such sugars or sugar alcohols include, but are not limited to, dextrose, mannitol, sorbitol, lactose, and sucrose. Of course, dextrose, for example, can exist as either a directly compressed sugar, i.e., a sugar that has been modified to increase compressibility, or an indirectly compressed sugar.

In general, the equilibrium formulation can be a matrix. Therefore, the filler percentage can reach 100%. However, in general, a useful amount of indirectly compressed filler in accordance with the present invention ranges from about 25 to about 95%, preferably between about 50 to about 95% and more preferably from about 60 to about 95%.

The amount of lubricant used may range from about 1 to about 2.5% by weight, and more preferably from about 1.5 to about 2% by weight. Useful hydrophobic lubricants in accordance with the present invention include alkaline stearates, stearic acid, mineral and vegetable oils, glyceryl behenate and sodium stearyl fumarate. Hydrophilic lubricants can also be used.

Useful protective materials in accordance with the embodiment of the present invention may contain any polymer commonly used in the form of microparticles, matrix-type microparticles and microcapsules. Among them are cellulosic materials such as cellulose in its natural form and derivatives of synthesized cellulose; acrylic polymers and vinyl polymers. Other simple polymers include proteinaceous materials such as gelatin, polypeptides, and natural and synthesized resins and waxes. The protective polymers can also be ethyl cellulose, methyl cellulose, carboxymethyl cellulose and a resinous acrylic material sold under the registered trademark EUDRAGIT by Rhone Pharma GmbH of Weiterstadt, Germany.

In addition to the previously mentioned ingredients, the matrix can also contain substances that help absorption, non-foaming disintegrants and foaming disintegrants. Substances that help absorption are compounds that can draw water into the dosage. They help transport moisture into the interior of the dosage. In this way, the dosage can be dissolved from the inside, as well as from the outside.

Any chemical that can transport moisture in the manner mentioned above can be considered a wicking agent. Absorption aids include a large number of traditional non-foaming disintegrants. These can be, 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, polymer and gum such as arabica and xanthan. Hydroxyalkyl cellulose such as hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose as well as compounds such as cabopol may also be used.

A typical percentage of non-foaming disintegrants used in conventional tablets can be as high as 20%. However, it is common for the amount of disintegrant used to be in the range of about 2 to about 5%, according to the Handbook of Pharmaceutical Excipients.

In accordance with this embodiment of the present invention, the amount of absorption aids used may range from 2 to about 12% and preferably from 2 to about 5%.

It is also possible that it contains non-foaming agents for decomposition which, if desired, do not have to transport moisture. In both cases, it is preferable to use either a rapidly water-soluble non-foaming disintegrant or a wicking agent and/or to minimize the use of conventional water-insoluble wicking agents or non-foaming disintegrants. If slow-dissolving, slow-water-soluble elements are used in sufficient quantity, the organoleptic properties of the tablets may deteriorate while they are dissolving in the mouth and therefore reduce their use. Of course, absorbents or non-foaming disintegrants that are rapidly water-soluble as mentioned herein can be used in larger amounts and will not contribute to the granularity of the formulation during dissolution. Preferred absorption aids according to the present invention may be cross-linked PVP, although their amounts must be controlled as they are not readily soluble in water.

In addition, it may be desirable to use the effervescent vapor, in combination with the other ingredients mentioned to improve the disintegration profile, organoleptic properties of the material and the like. Preferably, the effervescent couple is in an amount between about 0.5 and about 50%, and more preferably between about 3 and about 15% by weight, based on the weight of the finished tablet. It is especially desirable that the amount of foaming material be sufficient so that the evolved gas is less than about 30 cm, after exposure to the water environment.

The term "foaming steam" refers to ingredients that develop gas. Preferred effervescent vapors evolve gas in a chemical reaction that occurs upon exposure of the effervescent vapor for decomposition to water and/or saliva in the mouth. This reaction is usually the result of a reaction between a soluble acid source and an alkaline monohydrogen carbonate or another carbonate source. The reaction of these two main ingredients after contact with water or saliva produces carbon dioxide gas. Such water-activated materials must be stored under anhydrous conditions with little or no absorbed moisture or in a stable hydrated form, as exposure to water will prematurely degrade the tablet. Acid sources can be any that are safe for human consumption and can generally be food acids, antacid acids and hydrides such as, for example, citric, tartaric, maleic, fumaric, adipic and succeic. Carbonate sources can be solid carbonate and bicarbonate salt such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. Reactants that evolve oxygen or other gases that are safe for human consumption are also included.

In the case of a tablet that dissolves in the mouth in accordance with the present invention, it is desirable that the amount and type of disintegrating agent, effervescent or non-effervescent agent, or a combination thereof, be sufficient in a controlled amount so that the tablet provides a pleasant organoleptic sensation in the patient's mouth. In some cases, the patient should experience a distinct foaming or bubbling sensation as the tablet disintegrates in the mouth. In general, the total amount of absorbents, non-foaming disintegrants and foaming agents should be in the range of 0-50%. However, it should be noted that the formulations of the present invention will dissolve rapidly and therefore, the need for disintegrants is minimal. As shown in the examples, adequate hardness, friability and dissolution time can be achieved without foaming disintegrants or large amounts of absorption aids.

The use of an indirect compressed filler eliminates the need for many common process steps such as granulation and/or the need to procure much more expensive pre-granulated, compressed fillers. At the same time, almost dosing is a balance of performance and stability. It is robust enough to be produced in the usual way using direct pressing. It is robust enough to be stored in bulk. However, it quickly dissolves in the mouth, while the unpleasant feeling of ordinary disintegrating tablets is minimized.

Formulations in accordance with the subject embodiment can be made by a method that includes the following steps:

(a) forming a mixture of the active ingredient and a matrix consisting of an indirectly compressed filler and lubricant;

(b) compressing the mixture to form a mixture of hard, compressed, rapidly disintegrating dosage forms including the active ingredient, stored in an orally soluble matrix; and possible

(c) bulk dosage storage before packaging. In a preferred embodiment, the dosages are then packaged in such packages that at least one is contained in the package. In a particularly preferred embodiment, the dosages are then packaged in such a package that there are more than one per package. Direct compression is the preferred method of dosage formulation.

Other formulations known to deliver the active substance to the oral cavity for absorption are the dosage forms described in US-A-6200604, which contain an orally administered drug in combination with an effervescent agent used as a penetration enhancer to affect the permeation of the drug through the oral, sublingual and mucous membranes. gums. As part of the present invention, the drug is desmopressin, which is administered in some forms through the sublingual mucosa. In the formulation of this embodiment of the invention, effervescent agents alone or in combination with other penetration enhancers may be used, leading to an increase in the range and extension of the oral absorption of the active ingredient.

Dosage formulations in accordance with this embodiment of the invention should include an amount of effervescent agent which will aid in the penetration of the medicinal agent through the oral mucosa. The effervescent agent is preferably in an amount between about 5% and about 95% by weight, based on the weight of the finished tablet, and more preferably in an amount between about 30% and about 80% by weight. It is especially desirable that there is enough effervescent material so that the evolved gas is more than 5 cm³ but less than about 30 cm³, after exposing the tablet to the water environment.

The term "foaming agent" includes gas-evolving components. Preferred foaming agents develop gas in a chemical reaction that occurs upon exposure of the foaming agent (foaming vapor) to water and/or saliva in the mouth. This reaction is most often the result of a reaction between a soluble acidic source and a source of carbon dioxide such as alkaline carbonates and bicarbonates. The reaction of these two common components produces carbon dioxide gas upon contact with water or saliva. Such water-activated materials must be stored in a generally anhydrous state and with little or no moisture absorbed or in a stable hydrated form, so that exposure to water does not prematurely degrade the tablet. Sources of acidity can be anything that is safe for human consumption and can generally contain food acids, antacid acids and hydrides such as: citric, tartaric, maleic, fumaric, adipic, succeic. Carbon sources are dry solid salts of carbonates and bicarbonates such as: preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. Reactants that evolve oxygen or other gases and are safe for human use are also included.

Foaming agents useful in this embodiment of the present invention are not always based on a reaction in which carbon dioxide is evolved. Reactants that evolve oxygen or other gases that are safe for human consumption may also be contemplated within the scope of this invention. When foaming agents contain two co-reactive components, such as an acid source and a carbon source, it is desirable that both components react completely. For this reason, an equal proportion of components that ensures equal equivalents is desirable. For example, if the acid used is diprotic, then either double the amount of monoactive carbonic alkali or an equal amount of direactive alkali must be used for complete neutralization. However, in other embodiments of the present invention, the amount of the acid or carbon source may exceed the amount of the other ingredient. This can be useful for improving the taste or performance of a tablet with an excess of one of the ingredients. In this case, it is preferable that an additional amount of one of the ingredients remains unreacted.

Such dosages may contain, in addition to the amounts required for foaming, additional amounts of agents for regulating pH. For medicinal ingredients that are weak acids or weak bases, the pH of the aqueous environment can affect the relative concentrations of ionized and non-ionized forms of the medicinal ingredient present in solution according to the Henderson-Hasselbach equation. The pH of the solution in which the effervescent vapor is dissolved is slightly acidic due to the evolution of carbon dioxide gas. The pH of the environment, i.e. saliva in direct contact with the tablet or some other medicinal ingredient that can be dissolved, can be adjusted by incorporating means for regulating the pH in the tablet, which allows controlling a certain amount of ionized and non-ionized forms of the medicinal agent. In this way, the relevant dosages can be optimized for each individual medicinal product. If it is known or assumed that a non-ionized medicinal agent will be absorbed through cell membranes (absorption through the cell) it would be desirable to change the pH of the environment (within patient-tolerant ranges) to a level that favors ionized forms of the medicinal agent. Conversely, if the ionized forms dissolve faster, the environmental conditions should support the ionization.

The solubility in water of the medicinal ingredient should not be jeopardized by the foaming agent and the pH regulating agent, so that the dosage enables a sufficient concentration of the medicinal agent in non-ionized form. Therefore, the percentage of pH adjusting agent and/or foaming agent should be adjusted according to the medicinal agent.

A suitable pH adjusting agent for use in the present invention is any weak acid or weak base in excess of that required for foaming or, preferably, any buffer system that is not harmful to the mucosa. A suitable pH adjusting ingredient for use in the present invention may be, but is not limited to, any acid and alkali previously mentioned as a foaming agent, disodium hydrogen phosphate, sodium dihydrogen phosphate and equivalent potassium salts.

Preferably, the dosage of this embodiment of the present invention contains one or more other ingredients to improve the absorption of the pharmaceutical ingredient through the oral mucosa and to improve the dissolution profile and organoleptic properties of the dosage. For example, the contact surface between the dosage and the oral mucosa, and the retention time of the dosage in the oral cavity can be improved by including a bioadhesive polymer in the drug delivery system. See, for example, Mechanicstic Studies of Effervescent-Induced Permeability Enhancement, Jonathan Eichman (1997), which is incorporated herein by reference. Foaming, due to its ability to exfoliate the mucosa, will also enhance the retention time of the bioadhesive and thus increase the retention time during drug absorption. Some examples of the use of bioadhesives used in the present invention are, for example, Karbopol 934P, Na-CMC, Metocel, Polycarbofil (Noveon AA-1), HPMC, Na-alginate, Na-hyaluronate and other natural and synthesized bioadhesives.

In addition to foaming agents, dosages may, in accordance with this embodiment of the subject invention, also contain appropriate non-foaming agents for decomposition. Some examples of non-foaming disintegrants are: microcrystals, cellulose, croscarmellose sodium, crosprovidone, starches, corn starch, potato starch and their modified starches, sweeteners, clays such as bentonite, alginates, gums such as agar, guar, locust bean , caraway, pectin and tragacanth. Disintegrants may comprise up to 20 percent by weight or preferably between about 2 and about 10% of the total weight of the composition.

In addition to the particles, in accordance with this embodiment of the present invention, the dosages may contain additives for gliding, lubricants, binders, sweeteners, flavoring and coloring agents. Any common sweetener or flavoring can be used. A combination of sweeteners, flavor components, or sweeteners and flavor components may also be used.

Examples of binders that can be used are acacia, tragacanth, gelatin, starch, cellulosic materials such as methyl cellulose and sodium carboxymethyl cellulose, alginic acids and their salts, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars and similar. Binders can be used in an amount up to 60 percent by weight and preferably about 10 to about 40 percent of the total weight of the preparation.

Coloring agents are titanium dioxide, and suitable food colors such as those known as F.D.&C. dyes and natural coloring agents such as grape skin extract, red beet powder, beta-carotene, annatto, carmine, turmeric, paprika and so on. The amount of coloring agent used can range from about 0.1 to about 3.5 percent of the total weight of the composition.

Flavors selected from synthesized aromatic oils and flavor enhancers and/or natural oils, extracts of plants, leaves, flowers, fruits and the like and their combinations can be incorporated into the preparation. These can be cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil and Chinese cinnamon oil. Vanilla, citrus oils including lemon, orange, grape, lime and grapefruit, and fruit essences such as apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so on are also useful as flavoring agents. Flavors that have proven particularly useful are commercially available orange, grape, cherry, and chewing gum flavors and mixtures thereof. The amount of flavoring can depend on a number of factors, including the desired organoleptic effect. Flavors may be present in an amount ranging from about 0.05 to about 3 weight percent based on the total weight of the composition. Particularly preferred flavors are grape and cherry flavors and citrus flavors such as orange.

One aspect of the invention provides a solid, oral dosage form in a tablet suitable for sublingual administration. Filling excipients may be used to facilitate tablet formation. It is desirable that the fillers aid in rapid dissolution of the dosage in the mouth. Some examples of suitable fillers are: mannitol, dextrose, lactose, sucrose and calcium carbonate.

As described in US-A-6200604, tablets can be produced either by direct compression or wet granulation or any other manufacturing technique. Dosages are administered to humans or other mammals by placing the dosage in the patient's mouth and holding it in the mouth under the tongue (for sublingual formulation). The dosage begins to break down spontaneously due to moisture in the mouth. Decomposition, especially foaming, stimulates additional salivation which further promotes decomposition.

Although the formulations described above are within the scope of the present invention, the most preferred orodispersible pharmaceutical solid dosages according to the invention contain desmopressin and an open network of a matrix carrying desmopressin, an open network of a matrix containing a water-soluble or water-degradable carrier material that is inert to desmopressin.

Pharmaceutical dosage forms containing an open network matrix are known from GB-A-1548022, to which reference is made in the following details. Pharmaceutical dosages of the invention can be rapidly degraded by water. By "quickly decompose" it is understood that the formed particles are decomposed in water in 10 seconds. Preferably, the shaped particles degrade within 5 seconds or even two seconds or one second or less. Disintegration time was measured by a procedure equivalent to the tablet disintegration test, B.P. 1973 (Disintegration Test for Tablets, B.P. 1973). The process is described in GB-A-1548022 and shown later in the text.

Apparatus

A glass or suitable plastic tube 80 to 100 mm long, with an internal diameter of about 28 mm and an external diameter of 30 to 31 mm, closed at the bottom to form a basket with a disc of stainless metal gauze that meets the conditions for sieve No. 1.70.

A glass cylinder with a flat bottom and an internal diameter of about 45 mm containing no less than 15 cm of water at a temperature between 36° and 38°C.

The basket is centrally limited in the cylinder in such a way that it can be repeatedly raised and lowered in a certain way so that at the highest position the gauze just touches the surface of the water and at the lowest position the upper edge of the basket just becomes clear of water.

Method

Place the shaped piece in the basket and raise and lower it in such a way that the entire up and down movement is repeated in equal proportion thirty times a minute. The shaped pieces are decomposed when not a single particle that would pass through the gauze remains above it. There should be no particles left after 10 seconds.

The term "open matrix network" refers to a network of water-soluble and water-dispersible carrier material through which branched interstices are distributed. The open network matrix of the carrier material is generally of low density. For example, the density can be in the range of 10 to 200 mg/cc, ie 10/100 mg/cc, preferably 30 to 60 mg/cc. The density of the molded piece may be determined by the amount of active ingredient, or some other ingredient, included in the piece and may be above the above-mentioned desirable limits for the density of the open network of the matrix. The open network of the matrix, which is similar in structure to rigid foam, allows the liquid to enter the product through the cavities and penetrate into the interior. The penetration of the aqueous medium exposes the carrier material, both in the interior and the outer part, to the action of the aqueous medium in which the network of the carrier material is rapidly degraded. The open network structure of the matrix is porous in nature and enhances the degradation of the product compared to ordinary solid-form pharmaceutical dosage forms such as tablets, pills, capsules, suppositories and vagitories. Rapid decomposition results in rapid release of the active ingredient carried by the matrix.

The carrier material used in the product of the invention can be any water-soluble or water-dispersible material that is pharmaceutically acceptable or chemically inert and that is capable of forming an open matrix network that rapidly degrades. It is preferable to use a water-soluble material for the carrier, considering that the degradation of the open network of the matrix is the fastest when the product is placed in an aqueous environment. A particularly preferred carrier may consist of polypeptides such as gelatin, especially gelatin that has been partially hydrolyzed, for example by heating in water. For example, gelatin can be partially hydrolyzed by heating a solution of a in water, eg in an autoclave at about 120°C for up to 2 hours, eg from about 5 minutes to about 1 hour, preferably from about 30 minutes to about 1 hour. It is preferable to take hydrolyzed gelatin in concentrations of about 1 to 6% or 8% wt./vol., most preferably at 2 to 4%, for example 3% or at 4 to 6%, for example 5%. As shown in the examples, these concentrations refer to the total formulation before water removal, for example by lyophilization.

Although gelatin derived from mammals can be used, it has an unpleasant taste and therefore requires the use of sweeteners and flavor enhancers to mask the taste of the gelatin in addition to the sweeteners and flavor enhancers required to mask the taste of the active ingredient. Furthermore, the necessary heating process of mammalian-derived gelatin increases production time and generates heating costs that increase the overall cost of the process. Therefore, the use of fish gelatin, especially non-gelatinizing fish gelatin, is preferred, especially for desmopressin. Reference is made to WO-A-0061117 in the following details.

Other carrier materials that can be used instead of partially hydrolyzed gelatin or fish gelatin are for example polysaccharides such as hydrolyzed dextran, dextrin and alginates (eg sodium alginate) or a mutual mixture of the aforementioned carriers or with other carrier materials such as polyvinyl alcohol, polyvinyl pyrrolidine or acacia. Modified starch can also be used instead of gelatin, as described in WO-A-0044351, which is referred to in detail below.

Other carrier materials that can be added to, or in some cases replace, the above carriers are: gums such as tragacanth, xanthan, carrageenan and guar; vegetable glue including linseed glue and agar; polysaccharides and other carbohydrates such as pectin and starch and its derivatives, especially soluble starch and dextrates; water-soluble cellulose derivatives, such as hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose and hydroxypropyl cellulose, and carbomer.

A filler may also be present. Preferably, the filler also aids in rapid dissolution or dispersion of the dosage in the mouth. Some examples of applicable fillers are sugars such as mannitol, dextrose, lactose, sucrose and sorbitol. It is preferable to use the filler in concentrations of about 0 to 6%, or 8% wt./vol., most preferably from 2 to 4%, e.g. about 3%, or from 4 to 6%, e.g. about 5%. Again, these concentrations refer to the total formulation prior to water removal for example by lyophilization.

Pharmaceutical dosages of the invention may be in the form of molded pieces. In addition to the active ingredient(s), they may also include additional ingredients. For example, a pharmaceutical dosage form of the subject invention may contain pharmaceutically acceptable excipients. Such auxiliaries are, for example, coloring agents, flavor enhancers, preservatives (eg bacteriostatic agents) and the like. US-A-5188825 teaches that water-soluble active agents should be bound to an ion-exchange resin to form a sufficient water-soluble active ingredient/resin complex; although this may be applied herein (referred to in detail below in US-A-5188825) during the development of the subject invention it was discovered that water-soluble peptides such as desmopressin can be formulated in a solid dosage form of the invention without the need for binding to ion exchange resin. For hydrophobic peptides, which desmopressin is not, a surfactant may be present, as shown in US-A-5827541, which is referred to in detail below. For peptides with an unpleasant taste (which desmopressin is not), a fat such as lecithin may be present to improve patient acceptance, as described in US-A-6156339, which is referred to in detail below. Other ways to create flavor are the conversion of a soluble salt to a less soluble salt or to a free base, as described in US-A-5738875 and US-A-5837287, and the use of the process described in US-A-5976577 in which, before lyophilization, the solution of unwrapped and wrapped coarse particles of the pharmaceutical active ingredient(s) in the carrier material is cooled to reduce the viscosity and minimize the release of the active ingredient during the process, as well as after the decomposition of the form in the mouth, to minimize the bad taste of the peptide; in the following details, a review is made of the cited patents.

For insoluble or poorly soluble peptides having large particles, xanthan gum may be present, especially when the carrier is formed from gelatin because xanthan gum can act as a flocculating agent for gelatin, as described in US-A-561023, which is reviewed in the following details.

As disclosed in WO-A-9323017 one or more amino acids having about 2 to 12 carbon atoms may be present when the matrix is selected from the group consisting of gelatin, pectin, soy fiber proteins and mixtures thereof. In this formulation, the preferred amino acid is glycine, while the preferred matrix forming agent is gelatin and/or pectin; in a particularly preferred form, the dosage also contains mannitol.

All excipients will be selected to be pharmaceutically acceptable.

Pharmaceutical dosages of the subject invention can be prepared by the process described in GB-A-1548022, which comprises solvent sublimation from a preparation of a pharmaceutical substance and a solution of a carrier material in a solvent, the preparation being in a solid state in a mold.

It is preferable that the sublimation is carried out by lyophilization of the preparation containing the active ingredient and a solution of the carrier material in a solvent. The preparation may contain additional ingredients, such as those mentioned above. The solvent is preferably water but may contain a co-solvent (such as an alcohol eg tert-butyl alcohol) to improve the solubility of the chemical. The preparation may also contain a surface-active ingredient, for example Tween 80 (polyhydroxyethylene (20) sorbitan mono-oleate). A surface-active ingredient can help prevent the philophilized product from sticking to the mold wall. It can also help disperse the active ingredient.

The preparation may contain pH adjusting agents to regulate the pH of the solution in which the dosage is prepared, in a ratio of 3 to 6, preferably 3.5 to 5.5, and most preferably 4 to 5, for example 4.5 or 4.8. Citric acid is the preferred pH regulator, but others including hypochlorous acid, maleic acid can be used. Such non-volatile pH regulators will not be removed by lyophilization or other sublimation processes and may be present in the final product.

The mold may have a series of cylindrical or otherwise shaped recesses therein, each size corresponding to the desired size of the molded piece. Another possibility is that the size of the cavity in the mold can be larger than the desired piece size and after the content is freeze-dried the product can be cut to the desired size (for example thin wafers).

However, as described in GB-A-2111423, it is preferred that the mold is a recess in the sheet of film material. The film-material can contain more than one depression. The film material may be similar to that used in conventional blister packs used to pack oral contraceptive pills and similar forms of medication. For example, the film-material can be made of thermoplastic material with indentations created by thermoforming. The preferred film-material is polyvinyl chloride film. Film-material laminates can also be used.

In one embodiment, the mold contains a metal plate (eg, an aluminum plate) having one or more depressions. In a preferred process in which such a mold is used, the mold is cooled with a cooling medium (eg, liquid nitrogen or solid carbon dioxide). When the mold cools, a predetermined amount of water containing the carrier material, active ingredient, and other desired ingredients is filled into the cavity(s). When the contents of the cavity are frozen, the mold is subjected to low pressure and, if desired, a controlled application of heat to aid sublimation. The pressure can be below 0.3 mm Hg, for example 0.1 to 0.2 mm is preferred. The freeze-dried products can then be removed from the mold cavity and stored for future use, eg in air-tight containers or other suitable storage containers. Another possibility is that the lyophilized products can be surrounded by a film-material as described in GB-A-2111423.

Later developed processes useful for the preparation of pharmaceutical dosages in accordance with the invention are described in GB-A-2111423, to which reference is made in the following details. The process includes filling a preparation containing a predetermined amount of active ingredient and a solution of partially hydrolyzed gelatin in a mold, freezing the preparation in the mold by passing a gaseous cooling medium over the mold, and then sublimating the solvent from the frozen preparation so that a network of partially hydrolyzed gelatin carrying the active ingredient is formed.

To ensure uniform strength of the product, the walls or walls of the mold may be inclined outwards from the base and form an angle with the vertical of at least 5° on the surface of the preparation, as described in GB-A-2119246 referred to in the following details.

Alternatively or in addition to this, the pharmaceutical formulations of the subject invention may be prepared by a process as described in GB-A-2114440 which comprises freezing a composition comprising a solution in a first solvent of a water-soluble or water-dispersible carrier material which is inert to the active ingredient, sublimating the first solvent from the frozen composition so as to produce a product having a network of carrier material, adding to said product a solution or suspension of a second anhydrous solvent containing a predetermined amount of the active ingredient by allowing or causing the second solvent to evaporate. Reference is made to GB-A-2114440 in the following details.

Alternatively or additionally, pharmaceutical dosages of the subject invention may be prepared by a process as described in GB-A-2111184, which comprises the introduction of a liquid medium in the form of droplets below the surface of a cooling liquid which is maintained at a temperature below the freezing point, cooling liquid is immiscible with, and is inert to, the liquid medium and possesses a higher density than both the liquid medium and the resulting frozen particles so that as liquid medium droplets float upward toward the surface of the cooling liquid, they are frozen to form surface particles. Frozen surface particles can collect on or near the upper surface of the coolant. Reference is made to GB-A-2111184 in the following details.

Dosages according to the invention have improved bioavailability. They were intended to be taken orally, and are highly suitable for that role. They are quickly dispersed in the mouth and can, for example, be placed under the tongue (sublingually), or they can be placed on the tongue or next to the cheek or gums.

According to another aspect of the invention, the dosage described above is determined for use in medicine, particularly for incontinence, incontinence, primary nocturnal enuresis (PNE), nocturnal enuresis and central diabetes insipidus.

The invention provides a procedure for urinary retention, treatment or prevention of incontinence, primary nocturnal enuresis (PNE), nocturnal enuresis and/or central diabetes insipidus, a procedure comprising administering to the patient an effective or generally non-toxic amount of desmopressin in an orodispersible pharmaceutical dosage, for example in a dosage such as is described above. Other diseases or conditions that can be treated or prevented by desmopressin may also be contemplated within the scope of this invention. In this way, the invention extends to the use of desmopressin in the production of an orodispersible pharmaceutical formulation. The invention is extended to a package containing an orodispersible pharmaceutical dosage of desmopressin together with instructions to place the dosage in the patient's mouth. The invention is also related to the method of preparing packaged dosages of desmopressin, a method that contains the combination of an orodispersible pharmaceutical dosage of desmopressin and instructions to place the dosage in the patient's mouth. The instructions may be printed on the package surrounding the dosage when sold or given, or may be on the product leaflet or inserted into the package.

In addition to desmopressin, other peptides can be formulated into the formulations described above. The invention therefore extends to orodispersible pharmaceutical dosages of pharmaceutically active peptides.

According to a further aspect of the invention, a solid pharmaceutical dosage form is provided, for example for oral administration, the dosage form contains pharmaceutically active peptides and an open matrix network that carries the peptides, an open matrix network consisting of a water-soluble or water-dispersible carrier material that is inert to peptide.

Although oral vaccines made from fast-dissolving dosages are known from WO-A-9921579, there is no indication of a pharmaceutically active peptide continuing their activity after administration. Experimental work in WO-A-9921579 only demonstrates the presence of IgA antibodies to tetanus toxins in saliva following the administration of tetanus toxins as a fast-dissolving adjuvant in a vaccine formulation. The formulations of the subject invention are not vaccines and do not include auxiliaries.

Pharmaceutical dosages of this aspect of the invention contain pharmaceutically acceptable peptides. Such peptides may be directly active per se or may have one or more active metabolites, i.e. may be prodrugs for the primary or truly active base. Peptides may have for example from 2 to 20, preferably from 5 to 15 amino acid residues (at least some of which may be D-isomers, although L-isomers will generally predominate). Peptides may be linear, branched or cyclic and may have natural residues or substituents or residues or substituents that are mostly or never found in natural peptides or proteins. Pharmaceutically acceptable salts, simple adducts and tautomers are used if necessary.

Examples of peptides usefully formulated in accordance with the invention are somatostatin and its analogs including cyclo(MeAla-Tyr-D-Trp-Lys-Val-Phe) and cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe- GABA), enkephalins including Met5-enkephalin and Leu5-enkephalin, oxytocin analogs such as atosiban (1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin), GnRH analogs such as triptorelin (6-D-Trp-GnRH), leupyrrolide ([D-Leu6, Pro8-NHEt]-GnRH), degarelix (Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hydroorotyl) -D-4Aph-(Cbm)-Leu-Ilys-Pro-D-Ala-NH2, where 2Nal is 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 analogs described in US-A-5925730 and US-A-4072668, and vasopressin analogs such as desmopressin. It is particularly desirable to formulate in terms of the invention agonists of naturally active peptides, such as those described above, given that agonists can be active in smaller doses than antagonists.

The dose will be determined by the physician or clinical physician, depending on the nature of the peptide, the nature of the disease or condition being treated or prevented, and other factors.

The invention extends to the use of the peptide in the manufacture of a dosage as described above for the treatment or prevention of a disease or condition treatable or preventable by the peptide.

The invention also provides a method of treating or preventing a disease or condition treatable or preventable with a peptide, the method comprising administering to a patient an effective or generally non-toxic amount of the peptide in a dosage as described above.

The contents of each document referenced in this specification are incorporated herein by reference to the fullest extent permitted by law.

Preferred features of each aspect of the invention, and where appropriate and appropriate each embodiment of each aspect of the invention, are also for each aspect or embodiment, mutatis mutandis. In particular, it is intended that the aspects, features and embodiments of the invention described above, especially in connection with desmopressin, are also applicable to other peptides.

The invention will be illustrated in the following examples.

Example 1 200 μg orodispersible dosage of desmopressin

Spray-dried fish gelatin (4g) and mannitol (3g) were placed in a glass flask. Then buffered water (93g) was added and a solution was formed by stirring with a magnetic wand. The pH is checked and, if necessary, adjusted to 4.8 with citric acid.

A Gilson pipette may be used to add 500 mg of this solution to each of a series of preformed blister packs having pockets of approximately 16 mm in diameter. Blister laminate may contain PVC covered with PVdC. The dose units are then frozen at a temperature of -110°C in a freezing tunnel with a retention time of 3.2 minutes and the frozen units are then kept in an upright freezer for more than 1.5 hours at a temperature of -25°C (±5°C). . The units are then lyophilized overnight with an initial shell temperature of 10°C which rises to +20°C at a pressure of 0.5 mbar. With the units, the humidity can be controlled by the drying track and by controlling the humidity under pressure before lifting.

Thus, following the general procedure set forth in Example 1 of WO-A-0061117, an orodispersible dosage form of desmopressin was prepared using the following dosage unit ingredients:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg

Mannitol EP/USP (Roquette, Mannitol 35) 15 mg

Fish gelatin USNF/EP 20 mg

Citric acid (if needed) [pH regulator] q.s. (quantum sufficit) up to pH 4.8

Buffered water [Removed by drying]

Example 2 400 μg orodispersible dosage of desmopressin

The procedure of Example 1 was followed, except that the amount of desmopressin per dosage unit was 400 μg.

Example 3 800 μg orodispersible dosage of desmopressin

The procedure of Example 1 was followed, except that the amount of desmopressin per dosage unit was 800 μg.

Example 4 200 μg orodispersible dosage of desmopressin

Following the general procedure set forth in Example 1 of WO-A-0061117, an orodispersible dosage form of desmopressin was prepared using the following dosage unit ingredients:

Desmopressin (PolyPeptide laboratories, Sweden) 200 μg

Mannitol EP/USP (Roqette, Mannitol 35) 6 mg

Fish gelatin USNF/EP 10 mg

Citric acid (as needed) [pH regulator] q.s. pH 4.8

Buffered water [Removed by drying]

Example 5 400 μg orodispersible dosage of desmopressin

The procedure of Example 4 was followed, except that the amount of desmopressin per dosage unit was 400 μg.

Example 6 800 μg orodispersible dosage of desmopressin

The procedure of Example 4 was followed, except that the amount of desmopressin per dosage unit was 800 μg.

Comparative example 1 intravenous desmopressin solution

A desmopressin preparation for injection is usually prepared using the following ingredients:

Desmopressin (PolyPeptide laboratories, Sweden) 4 mg

Sodium chloride

(National Corporation of Swedish Pharmacies, Sweden) 9 mg

Hydrochloric acid (1N) (Merck, Germany) q.s. to pH 4

Water for injection q.s. up to 1 ml

Comparative example 2 200 μg of a common desmopressin tablet

Using a conventional wet granulation process, tablets containing the following ingredients were produced:

Desmopressin (PolyPeptide laboratories, Sweden) 200 μg

Lactose (Pharmatose 150M, DMV, Netherlands) 120 mg

Potato starch (Lyckeby AB, Sweden) 77 mg

PVP (Kollidon 25, BASF, Germany) 1.8 mg

Magnesium stearate (Peter Greven, Germany) 1 mg

Granulation liquid (water, ethanol) [Removed by drying]

Comparative example 3 100 μg common desmopressin tablet

The procedure of Comparative Example 2 was followed, except that the amount of desmopressin per dosage unit was 100 μg.

Example 7 Bioavailability of desmopressin administered according to examples 4 to 6

Performance of the study

Twenty-four non-smoking male volunteers were included in this study. The study was performed as a centered, open-label, randomized, balanced, 4-fold crossover first phase of the study. Each subject was randomized to receive desmopressin sublingually as 200 μg, 400 μg, and 800 μg orodispersible dosage (as in Examples 4, 5, and 6) and 2 μg as an intravenous bolus dose (Comparative Example 1). There was a 72-hour washout period between doses. In order to standardize the oral mucosa before administration of the orodispersible tablet, the subject was asked to avoid food, chewing gum, etc. The subject was allowed to brush his teeth in the morning before dosing, but without toothpaste.

Blood samples

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

Essay

Desmopressin concentration in plasma was determined by the approved RIA method.

Pharmacokinetic analysis

Plasma desmopressin concentration was analyzed for each volunteer in each application group, using unbiased methods using the commercially available software WinNonlin™ Pro, ver. 3.2 (Pharsight Corporation, USA). Plasma concentration values below the limits of quantitation (LOQ) followed by values above the LOQ set to 'LOQ/2' for NCA analyzes and for descriptive statistics of concentrations. Values below the LOQ that were not followed by values above the LOQ were excluded from the NCA analyses, and set to zero in the descriptive statistics of concentrations.

Results of pharmacokinetic analyses

After intravenous administration, the average volume of distribution in steady state (Vss) was 29.7 dm³. Average cleaning is calculated at 8.5 dm³/hour. and the average elimination half-life was determined to be 2.8 hours. After oral administration of desmopressin, the maximum plasma concentration was observed at 0.5-2.0 hours after dosing. The maximum plasma concentration was 14.25, 30.21 and 65.25 pg/ml after the oral dose, which refer to the application of the dose of 200, 400 and 800 μg. After reaching the maximum value, desmopressin was eliminated with an average elimination half-life in the range of 2.8-3.0 hours.

Bioavailability was determined to be 0.30% with a 95% confidence interval of 0.23-0.38%.

The pharmacokinetics of desmopressin is linear, when administered if the orodispersible dosage of examples 4, 5 or 6.

Comparative Example 4 Bioavailability of desmopressin administered in accordance with Comparative Examples 2 and 3

Thirty-six non-smoking male volunteers (white, black, and Hispanic) were enrolled in this study, which was conducted as an open-label, single-dose, 3-fold crossover study. Each subject was administered, in random order, 200 μg of desmopressin as a single 200 μg tablet (Comparative Example 2), 200 μg of desmopressin as two 100 μg tablets (Comparative Example 3), and 2 μg as an intravenous bolus dose (Comparative Example 1).

After intravenous administration, the average half-life of elimination was determined to be 2.24 hours. After oral administration of desmopressin, the maximum plasma concentration was measured at 1.06 hours (2 x 100 μg) or 1.05 hours (1 x 200 μg) after dosing. The maximum plasma concentration was 13.2 and 15.0 pg/ml after an oral dose, which refer to the administration of doses of 2 x 100 μg and 1 x 200 μg. The determined bioavailability was 0.13% (2 x 100 μg) or 0.16% (1 x 200 μg).

Claims (27)

1. Orodispersible dosing of desmopressin. 2. Dosing in accordance with claim 1, characterized in that it is in an orodispersible pharmaceutical dosage. 3. A solid pharmaceutical dosage form containing desmopressin and an open network of a matrix carrying desmopressin, an open network of the matrix consisting of a water-soluble or water-dispersible carrier material that is inert to desmopressin. 4. Dosing according to claim 3, characterized in that the open network of the matrix contains gelatin. 5. Dosage according to claim 4, characterized in that the gelatin is fish gelatin. 6. Dosing in accordance with claim 5, characterized in that the fish gelatin is non-gelatinizing. 7. The process of preparing a solid pharmaceutical dosage contains the sublimation of a solvent from a preparation containing desmopressin and a solution of a carrier material in a solvent, the preparation being in a solid state in a mold. 8. The process according to claim 7, characterized in that the sublimation is performed by lyophilization of the preparation containing desmopressin and a solution of the carrier material in the solution. 9. Process according to claim 7 or 8, characterized in that the solvent is water. 10. The process according to claim 7, 8 or 9, characterized in that the pH of the solution is in the range from 3 to 6, preferably 3.5 to 5.5, and most preferably from 4 to 5. 11. Dosage in accordance with any of claims 1 to 10, indicated that it is for use in medicine. 12. Dosage according to any one of claims 1 to 10, indicated that it is for use in urinary incontinence, or treatment or prevention of incontinence, primary nocturnal enuresis (PNE), nocturnal enuresis or central diabetes insipidus. 13. Use of desmopressin in the production of orodispersible pharmaceutical dosage. 14. A method of treating or preventing a disease or condition that is curable or preventable with desmopressin, a method comprising the use of an orodispersible pharmaceutical dosage in an effective and generally non-toxic amount of desmopressin for the subject. 15. The method according to claim 14, characterized in that the method is urinary retention, or treatment or prevention of incontinence, primary nocturnal enuresis (PNE), nocturnal enuresis and/or central diabetes insipidus. 16. Packaging containing an orodispersible pharmaceutical dosage of desmopressin together with instructions for placing the dosage in the patient's mouth. 17. Process for preparing a packaged dosage of desmopressin, a process that combines an orodispersible pharmaceutical dosage of desmopressin and instructions for placing the dosage in the patient's mouth. 18. Orodispersible pharmaceutical dosage from a pharmaceutically active peptide. 19. Dosage according to claim 18, characterized in that it is a solid orodispersible pharmaceutical dosage. 20. A solid pharmaceutical dosage form containing a pharmaceutically active peptide and an open network matrix carrying the peptide, the open network matrix consisting of a water-soluble or water-dispersible carrier material that is inert to the peptide. 21. Dosage according to any one of claims 18 to 20, characterized in that the peptide is somatostatin or its analogue, enkephalin, oxytocin analogue, LH-RH analogue, GnRH analogues or vasopressin analogues. 22. Dosage according to claim 20, characterized in that the open network of the matrix contains gelatin. 23. Dosage according to claim 22, characterized in that the gelatin is fish gelatin. 24. Dosage according to claim 23, characterized in that the fish gelatin is non-gelatinizing. 25. A process for preparing a solid pharmaceutical dosage containing a pharmaceutically active peptide, a process comprising sublimation of a solvent from a composition containing a peptide and a solution of a carrier material in a solvent, the composition being in a solid state in a mold. 26. The process according to claim 25, characterized in that the sublimation is performed by lyophilization of the preparation containing the peptide and the solution of the carrier material in the solution. 27. Dosage in accordance with any of claims 18 to 24, characterized in that it is for use in medicine.