CN102166345A - Pharmaceutical composition comprising low dose desmopressin - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising 0.5ng-20μg desmopressin and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition comprising desmopressin and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is effective to establish from about 0.1 pg desmopressin/mL plasma/serum to about 10.0 pg desmopressin Stable plasma/serum desmopressin concentration of desmopressin/mL plasma/serum. Products and methods of manufacture using the above inventions are also disclosed.

Description

Pharmaceutical composition comprising low dose desmopressin

This application is a divisional application of the Chinese invention patent application with the application number 200380110675.1, the application date is November 10, 2003, and the invention title is "Pharmaceutical Composition Containing Low Dose Desmopressin".

technical field

The present invention relates to pharmaceutical compositions comprising desmopressin, and more particularly to pharmaceutical compositions comprising low doses of desmopressin for the treatment of specific human diseases.

Background technique

Desmopressin (1-deamino-8-D-arginine vasopressin, dDAVP) is an analog of vasopressin. Desmopressin has decreased vasopressor activity and increased urostatic activity compared to vasopressin. This pharmacological property allows desmopressin to be clinically used for urinary control without causing a significant increase in blood pressure. Desmopressin acetate is commercially available in tablet and nasal spray forms and is commonly used for delayed voiding, incontinence, primary nocturnal enuresis (PNE) and nocturia, among other indications, including central Prescription for diabetes insipidus.

Desmopressin has been administered intravenously, subcutaneously, intranasally and orally. The intravenous route of administration is used clinically almost exclusively in patients with mild hemophilia or von Willebrand's disease to elevate blood levels of Factor VIII prior to surgery. Subcutaneous injection is rarely used and is mainly used in patients with central diabetes insipidus, insufficient vasopressin causes the kidneys to produce large volumes of very dilute urine, which can cause severe dehydration. Intranasal administration of desmopressin via nasal spray is approved for the maintenance treatment of patients with central diabetes insipidus and children (6-16 years) with primary nocturnal enuresis. The oral tablet form of desmopressin is also approved for the treatment of central diabetes insipidus and primary nocturnal enuresis.

Currently, approved labels for desmopressin recommend dosing within the following ranges, depending on the clinical indication and route of administration:

Typically a 20 microgram (mcg or μg) intranasal dose of desmopressin for CDI or PNE achieves a maximal plasma/plasma/serum concentration of about 20-30 pg/mL based on 3-5% bioavailability. The bioavailability of desmopressin oral tablets is only 0.1-0.15%, and standard doses of 200-400mcg also yield peak plasma/plasma/serum levels of 20-30pg/mL.

Although existing formulations of desmopressin have met the needs of patients, improvements are still needed. Patients often prefer tablets because of their ease of use, discreteness, and lack of uncertainty about correct dosing. However, tablets usually need to be taken with a glass of water or other beverage. The problem with desmopressin therapy is that fluid intake is restricted. The patient message is clearer when no water is ingested at all. Furthermore, while the doses and plasma/plasma/serum concentrations described above are effective in the treatment of CDI and PNE, standard doses of desmopressin have been shown to cause adverse side effects, including a high incidence of hyponatremia. Lower dosages are preferred if the same desired effect can be produced. However, the current trend in the field is to evaluate higher doses of desmopressin for therapeutic purposes.

Contents of the invention

In one aspect, the present invention relates to a pharmaceutical composition comprising 0.5ng-20μg desmopressin and a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to a pharmaceutical composition comprising desmopressin and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is effective to establish about 0.1 pg desmopressin/mL plasma/plasma/serum to A steady plasma/plasma/serum desmopressin concentration of approximately 10.00 pg desmopressin/mL plasma/plasma/serum.

In another aspect, the invention relates to an article of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said pharmaceutical composition is therapeutically effective for the treatment or prevention of hemophilia, von Weiler Brand's disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, and wherein the packaging material includes instructions for explaining that the pharmaceutical composition can be used for the treatment or prevention of hemophilia, von Willebrand's disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, and wherein the pharmaceutical composition comprises 0.5ng-2μg desmopressin and a pharmaceutically acceptable Accept carrier.

In another aspect, the present invention relates to a method of treating or preventing a disease or condition treatable or preventable by desmopressin, said method comprising administering to a patient a daily dose of a therapeutically effective amount of desmopressin containing 0.5ng-20μg desmopressin The pharmaceutical composition of element and pharmaceutically acceptable carrier.

In another aspect, the present invention relates to a method for inducing diuria in a patient, comprising the step of administering to the patient a daily dose of a therapeutically effective amount of a pharmaceutical composition comprising 0.5 ng-20 μg of desmopressin and a pharmaceutically acceptable carrier .

These and other aspects will be apparent upon reading the following detailed description of the invention.

Description of drawings

The present invention will be more fully understood from the following detailed description, in conjunction with the accompanying drawings, in which:

Figure 1 shows the urine osmolality of each experimenter given 0.5ng/kg desmopressin;

Figure 2 shows the urine osmolality of each experimenter given 1.0 ng/kg desmopressin;

Figure 3 shows the urine osmolality of each experimenter given 2.0 ng/kg desmopressin;

Figure 4 shows the urine output of each experimenter given 0.5ng/kg desmopressin;

Figure 5 shows the urine output of each subject administered 1.0 ng/kg desmopressin;

Figure 6 shows the urine output of each subject administered 2.0 ng/kg desmopressin;

Figure 7 shows mean urine osmolality for administration of 0.5, 1.0 and 2.0 ng/kg desmopressin;

Figure 8 shows urine output after administration of 0.5, 1.0 and 2.0 ng/kg desmopressin; and

Figure 9 shows mean urine osmolality and mean urine output for administration of 0.5, 1.0 and 2.0 ng/kg desmopressin.

Detailed description of the invention

It has now been found that desmopressin can be administered as a solid dosage form which is absorbed orally and has increased bioavailability. It is surprising that desmopressin can be completely absorbed in this manner, since the evidence obtained shows that desmopressin administered orally (sublingually) is not absorbed in large quantities (Fjellestad-Paulsen A. et al. People, Clin. Endocrinol. 38177-82 (1993)). Even less unexpected is that the bioavailability could be improved compared to conventional oral tablets (ie swallowed by the patient).

It has also been surprisingly found that low doses and low plasma/plasma/serum levels of desmopressin are pharmacologically active and achieve the desired therapeutic effect. The inventors have found that doses and plasma/plasma/serum concentrations of desmopressin which are 5-40% of the currently recommended doses and resulting plasma/plasma/serum levels are therapeutically effective and in some cases CDI, PNE, and other clinical indications requiring pharmacologically concentrated urine are safer. The actual dose-response curve for desmopressin was found to be shifted to the left relative to current theory and practice and increased pharmacological effects were observed in urine concentrations at each plasma/plasma/serum concentration point within the predicted dose range.

A first aspect of the present invention provides a pharmaceutical dosage form of desmopressin suitable for sublingual absorption.

Desmopressin may be in free base or pharmaceutically or, if desired, veterinarily acceptable salt form, or any other pharmaceutically or veterinarily acceptable form. Acetate is particularly preferred.

The formulation is usually a solid. It disperses rapidly in the oral cavity. Such formulations are referred to as "orodispersible". The formulation will generally contain a suitable carrier for the purpose, which is pharmaceutically acceptable (or, in the case of administration to an animal other than human, veterinarily acceptable).

Daily doses of desmopressin measured in the free base form are usually 0.5 or 1 μg to 1 mg per dosage form. In one of the preferred dosage ranges, the dosage is generally 2 μg-800 μg per dosage form and preferably 10 μg-600 μg. Lower dosages (e.g., lower dosages relative to the dosages described above or provided by the prior art), such as 0.5ng to 20,000ng, preferably 0.05mcg (50ng) to 10mcg (10,000ng), are also specifically contemplated. Preferably 0.1 mcg (100 ng) - 2000 ng. When one dosage form is given daily, usually for PNE and nocturia, generally a dose of each dosage form. When the daily dose is administered in two or more doses, as is usually the case for central diabetes insipidus, the amount of active compound per dosage form will be reduced accordingly. Effective daily dosages will depend on the condition of the individual patient, and thus can be determined for any particular patient by one of ordinary skill in the art. Other active ingredients, whether peptides or not, may also be present.

The pharmaceutical dosage form according to the invention is suitable for delivering the active ingredient to the oral cavity. The active ingredient can be distributed systemically by absorption through the sublingual mucosa.

Various formulations suitable for delivery of other active ingredients for absorption from the oral cavity are known. Such formulations are useful in the present invention. They are orally disintegrating solid preparations or products comprising the active ingredient, sugars containing lactose and/or mannitol, agar at 0.12-1.2w/w% of the solid content, having a concentration of 400mg/ml-1,000mg/ml The density in ml and the strength sufficient for handling, which in practice may mean sufficient strength to be removed from the blister pack without shattering. Such formulations, and how to prepare them, are disclosed in US-A-5466464, to which reference is made for further details.

In this embodiment of the present invention, at least 50w/w% of total solid content, preferably 80w/w% or more, more preferably 90w/w% or more of sugar can be used in the formulation, and it can be used according to the activity used. The quality and quantity of ingredients vary.

Although there is no particular limitation on the type of agar, those listed in the Japanese Pharmacopoeia can be preferably used. Examples of the listed agars include agar powder PS-7 and PS-8 (manufactured by Ina Shokuhin).

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

To produce the formulation of this embodiment of the invention, sugars containing lactose and/or mannitol are suspended in an aqueous agar solution, filled with a mold, solidified into a jelly-like form, and then dried. The aqueous agar solution may have a concentration of 0.3-2.0%, preferably 0.3-0.8%. The agar aqueous solution can be used in the following amount, that is, based on solid content, the mixing ratio of agar is 0.12-1.2w/w% based on solid content, but preferably 40-60w/w% agar solution.

Other formulations known to deliver active ingredients for absorption from the oral cavity are the dosage forms disclosed in US-A-6024981 and US-A-6221392. They are hard, compressed, fast-dissolving forms suitable for direct oral administration, comprising: active ingredients and a matrix including indirect compression fillers and lubricants, the dosage form is suitable for rapid dissolution in the patient's mouth and release therefrom The active ingredient, and when tested according to U.S.P., has a friability of about 2% or less, and the dosage form 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 characteristics of these dosage forms and how to prepare them.

Preferably, the dosage form of this embodiment of the invention dissolves in the oral cavity of the patient in about 90 seconds or less, preferably 60 seconds or less and most preferably 45 seconds or less. It is also often desirable that the dosage form includes at least one particle. The granules are the active ingredient and protective substance. These granules may include immediate release granules and or sustained release granules.

In a particularly preferred formulation of this embodiment of the invention, a hard, compressed, fast-dissolving tablet suitable for direct oral administration is provided. The tablet consists of granules made of active ingredient and protective substance. These granules are provided in an amount of from about 0.01 to about 75% by weight of the tablet. The tablet also includes a matrix made of an indirect compression filler, a wicking agent and a hydrophobic lubricant. The tablet matrix comprises at least about 60% by weight of the total matrix material of rapidly water-soluble ingredients. The tablet has a hardness of about 15 to about 50 Newtons when measured by U.S.P., a friability of less than 2%, and is adapted to naturally dissolve in a patient's mouth in less than about 60 seconds and thereby release the Granules and can be stored in bulk.

Very finely divided granulated or powdered sugars, which are considered to be indirect compressed sugars, can be used as bulking agents in the matrix of this embodiment of the invention. This substance, partly due to its chemical composition and partly due to its fine particle size, will readily dissolve in the oral cavity in the order of seconds or so, once wetted with saliva. Not only does this mean that it can aid in the dissolution rate of the dosage form, but it also means that when the patient retains the dissolved dosage form in his or her mouth, the filler will not provide a "grainy" or "gritty" texture rather than a "gritty" texture. The organoleptic sensation of taking the dosage form is thus adversely affected. In comparison, direct compressed forms of the same sugar are usually pelletized and processed to make them larger and better compacted. When these sugars are water soluble, they cannot be solidified quickly enough. As a result, they can impart a granular or sandy texture to the dosage form as they dissolve. The dissolution time in the oral cavity can be measured by observing the dissolution time of the tablet in water at about 37°C. Submerge the tablet in water with no or minimal agitation. Dissolution time is the time from submersion to substantially complete dissolution of rapidly water-soluble ingredients in the tablet, as determined by visual inspection.

Particularly preferred bulking agents according to the invention are indirect compression sugars and sugar alcohols, which meet the specific requirements discussed above. Such sugars and sugar alcohols include, but are not limited to, glucose, mannitol, sorbitol, lactose and sucrose. Of course, glucose, for example, may be present as a direct compression sugar, ie a sugar which has been modified to increase its compressibility, or as an indirect compression sugar.

Typically, the balance of the formulation will be the matrix. Therefore, the percentage of filler can approach 100%. Typically, however, the amount of indirect compression filler used in the present invention is from about 25 to about 95%, preferably from about 50 to about 95%, and more preferably from about 60 to about 95%.

The amount of lubricant used is generally from about 1 to about 2.5% by weight, and more preferably from about 1.5 to about 2% by weight. Hydrophobic lubricants useful in the present invention include alkaline stearates, stearic mineral and vegetable oils, glyceryl behenate and sodium stearyl fumarate. Hydrophilic lubricants can also be used.

The protective material used in this embodiment of the invention may comprise any of the polymers conventionally used in the formation of microparticles, matrix-type microparticles and microcapsules. These are cellulosic substances such as naturally occurring cellulose and synthetic cellulose derivatives; acrylic polymers and vinyl polymers. Other simple polymers include proteinaceous substances such as gelatin, polypeptides and natural and synthetic shellacs and waxes. Protective polymers may also include ethylcellulose, methylcellulose, carboxymethylcellulose and acrylic resin materials sold by Rhone Pharma GmbH of Weiterstadt, Germany under the registered trademark EUDRAGIT.

In addition to the previously discussed ingredients, the matrix may also include a wicking agent, a non-effervescent disintegrant, and an effervescent disintegrant. A wicking agent is a composition capable of introducing water into a dosage form. They help transport moisture to the interior of the dosage form. In this way, the dosage form can be dissolved from the inside as well as from the outside.

As discussed above, any chemical that can function to transport moisture can be considered a wicking agent. Wicking agents include many traditional non-effervescent disintegrants. These include, for example, microcrystalline cellulose (AVICEL PH 200, AVICEL PH 101), Ac-Di-Sol (croscarmellose sodium) and PVP-XL (cross-linked polyvinylpyrrolidone); starches and modified Starches, polymers and gums such as gum arabic and xanthan. Hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, and compounds such as carbopol can also be used.

Typical ranges for non-effervescent disintegrants used in conventional tablets can be as high as 20%. Generally, however, disintegrants are used in an amount ranging from about 2 to about 5%, according to the handbook of pharmaceutical excipients.

According to this embodiment of the invention, the amount of wicking agent used may range from 2 to about 12% and preferably from 2 to about 5%.

Of course, non-effervescent disintegrants may also be included, if desired, which may not function to introduce moisture. In either case, the use of rapidly water-soluble non-effervescent disintegrants or wicking agents is preferred and/or the use of normally water-insoluble wicking agents or non-effervescent disintegrants is minimized. Non-rapidly soluble, non-rapidly water-soluble ingredients may adversely affect the organoleptic properties of the tablet when dissolved in the oral cavity if used in sufficient amounts, so their use should be minimized. Of course, the rapidly water-soluble wicking agents or non-effervescent disintegrants discussed here can be used in large quantities and should not be added to the sand-like formulation during the dissolution process. Preferred wicking agents of the present invention include cross-linked PVP, although the amount of these wicking agents must be controlled because they do not dissolve rapidly in water.

In addition, it may be desirable to use an effervescent couple, in combination with other listed ingredients to improve the disintegration, organoleptic properties, etc. of the material. Preferably, the effervescent couple is provided in an amount of from about 0.5 to about 50%, and more preferably from about 3 to about 15%, by weight of the finished tablet. It is especially preferred to provide sufficient effervescent material such that less than about 30 cm of gas is evolved after contact with an aqueous environment.

The term "effervescent couple" includes compounds that evolve gas. Preferred effervescent pairs are gassed by a chemical reaction that occurs upon contact of the effervescent disintegrating pair with water and/or saliva in the oral cavity. This reaction is most often the result of the reaction of a soluble acid source with an alkaline monobicarbonate or other carbonate source. The reaction of these two common compounds produces carbon dioxide gas after contact with water or saliva. Such water-activated materials must remain in a generally anhydrous state and absorb little or no moisture or exist in a stable hydrated form, since contact with water will prematurely disintegrate the tablet. The acid source may be any acid safe for human use and may generally include food acids, acids and hydrite antacids such as: citric, tartaric, malic, fumaric, adipic and succinic acids. Carbonate sources include dry solid carbonates and bicarbonates such as, preferably, sodium bicarbonate, sodium carbonate, potassium and potassium bicarbonates, magnesium carbonate, and the like. Reactants that evolve oxygen or other gases safe for human use may also be included.

In the case of the orally dissolving tablet of the present invention, preferably the amount and type of effervescent or non-effervescent disintegrants and combinations thereof are provided in sufficient controlled amounts such that the tablet provides a pleasant organ in the mouth of the patient. Feel. In some cases, patients should be able to feel the distinct sensation of bubbling or bubbling as the tablet disintegrates in the mouth. Typically, the total amount of wicking agent, non-effervescent disintegrant and effervescent disintegrant should be 0-50%. However, it should be emphasized that the formulations of the invention will dissolve rapidly and therefore, the need for disintegrants is minimal. As illustrated in the examples, suitable hardness, friability and dissolution time can still be obtained even without effervescent disintegrant or higher levels of wicking agent.

The use of non-direct compression fillers eliminates the need for many conventional processing steps such as granulation and/or purchase of more expensive pre-granulated, compressible fillers. At the same time, the resulting dosage form is a balance of performance and stability. Conventional production using direct compression is sufficient. Sufficient for bulk storage or packaging. Also, it dissolves rapidly in the mouth while minimizing the unpleasant sensation of conventional disintegrating tablets.

Formulations of embodiments of the invention may be manufactured by a process comprising the following steps:

(a) forming a mixture comprising the active ingredient and a matrix comprising fillers and lubricants for indirect compression;

(b) compressing the mixture to form a plurality of hard, compressed, rapidly disintegrating dosage forms comprising the active ingredient distributed in an orally dissolvable matrix; and optionally

(c) The dosage form is stored in bulk prior to packaging.

In a preferred embodiment, the dosage forms are enclosed within the cavity of a pack such that each pack contains at least one. In a particularly preferred embodiment, the dosage forms are enclosed within the cavity of a pack such that each pack contains more than one. Direct compression is the preferred method of forming this dosage form.

Other formulations known for delivering active ingredients for absorption from the oral cavity are the dosage forms disclosed in US-A-6200604, which comprise an orally administrable drug and an effervescent agent which acts as a penetration enhancer and Affects the permeability of drugs through the oral, sublingual and gingival mucosa. In the context of the present invention, the drug is desmopressin, which in most embodiments is administered sublingually. In formulations of this embodiment of the invention, effervescent agents may be used alone or in combination with other penetration enhancers which result in an increase in the rate and extent of oral absorption of the active drug.

The formulation or dosage form of this embodiment of the invention should include an effective amount of an effervescent agent to facilitate penetration of the drug through the oral mucosa. Preferably, the effervescent agent is provided in an amount of from about 5% to about 95% by weight of the finished tablet, and more preferably from about 30% to about 80% by weight. It is especially preferred to provide a sufficient amount of effervescent material such that more than about 5 cm ³ of gas is evolved but less than about 30 cm ³ after the tablet is contacted with an aqueous environment.

The term "effervescent" includes compounds which evolve gas. Preferred effervescent agents evolve gas through a chemical reaction that occurs upon contact of the effervescent agent (effervescent couple) with water and/or saliva in the oral cavity. This reaction is most often the result of the reaction of a soluble acid source with a carbon dioxide source such as an alkaline carbonate or bicarbonate. The reaction of these two common compounds produces carbon dioxide gas after contact with water or saliva. Such water-activated materials must remain in a generally anhydrous state and absorb little or no moisture or remain in a stable hydrated form, since contact with water will prematurely disintegrate the tablet. The acid source may be any acid safe for human use and may generally include food acids, acids and hydrite antacids such as: citric, tartaric, malic, fumaric, adipic and succinic acids. Carbonate sources include dry solid carbonates and bicarbonates such as, preferably, sodium bicarbonate, sodium carbonate, potassium and potassium bicarbonates, magnesium carbonate, and the like. Reactants that evolve oxygen or other gases safe for human use may also be included.

The effervescent agents used in this embodiment of the invention are not always based on a carbon dioxide forming reaction. Reactants that evolve oxygen or other gases safe for human use are also considered to fall within this range. When the effervescent agent comprises two components which react with each other, such as an acid source and a carbonate source, it is preferred that the two components react completely. Therefore, it is preferable to provide an equivalent ratio of components of equal equivalents. For example, if the acid used is binary, then twice the amount of monoreactive carbonate base, or an equal amount of direactive base, should be used to achieve complete neutralization. However, in other embodiments of the invention, the acid or carbonate source may be used in excess of the other ingredients. This can be used to improve the taste and/or performance of tablets containing excess of either ingredient. In such cases, additional amounts of either ingredient to remain unreacted are acceptable.

Such dosage forms may also include additional amounts of pH-adjusting substances required for effervescence. For weakly acidic or weakly basic drugs, the pH of the aqueous environment can affect the relative concentrations of ionized or non-ionized forms of the drug present in solution according to the Henderson-Hasselbach equation. The pH of the solution in which the effervescent couple had been dissolved was slightly acidic due to the evolution of carbon dioxide. The pH of the local environment, such as saliva, which is in immediate contact with the tablet and any drug that dissolves, can be adjusted by incorporating pH adjusting substances in the tablet, thereby controlling the relative fraction of the ionized and non-ionized forms of the drug. In this way, existing dosage forms for each specific drug can be optimized. If it is known or suspected that a non-ionized drug is absorbed through cell membranes (transcellular uptake), it is preferable to alter the pH of the local environment (within limits tolerated by the subject) to a level that favors the non-ionized form of the drug. Conversely, if the ionized form is more soluble, the local environment should favor ionization.

The water solubility of the drug should preferably not be impaired by effervescent and pH adjusting substances so that the dosage form allows sufficient concentrations of the drug to be present in non-ionized form. Therefore, the percentage of pH adjusting substance and/or effervescent should be adjusted according to the drug.

Suitable pH adjusting substances for use in the present invention include any weak acid or base in the additional amount required for effervescence or, preferably, any buffer system which is not detrimental to the oral mucosa. Suitable pH adjusting substances for use in the present invention include, but are not limited to, any of the acids or bases previously mentioned for effervescent compounds, such as disodium hydrogen phosphate, sodium dihydrogen phosphate and equivalent potassium salts.

The dosage form of this embodiment of the invention preferably includes one or more additional ingredients to enhance the absorption of the pharmaceutical ingredient through the oral mucosa and to enhance the disintegration and organoleptic properties of the dosage form. For example, the contact area between the dosage form and the oral mucosa, the residence time of the dosage form in the oral cavity can be improved by including bioadhesive polymers in the drug delivery system. See, eg, Mechanistic Studies on Effervescent-Induced Permeability Enhancement by Jonathan Eichman (1997), which is incorporated herein by reference. Effervescence, due to its muco-peeling properties, can also increase the residence time of bioadhesives, thereby increasing the residence time for drug absorption. Non-limiting examples of bioadhesives useful in the present invention include, for example, Carbopol 934P, Na CMC, Methocel, Polycarbophil (Noveon AA-1), HPMC, algal sodium hyaluronate, sodium hyaluronate, and other natural or synthetic bioadhesives.

In addition to the effervescent agent, the dosage form of this embodiment of the invention may also include a suitable non-effervescent disintegrant. Non-limiting examples of non-effervescent disintegrants include: microcrystalline cellulose, croscarmellose sodium, polyvinylpolypyrrolidone, starch, corn starch, potato starch and its modified starches, sweeteners, clays , such as bentonite, alginates, gums such as agar-agar, guar, locust bean, karaya, pectin and tragacanth. The disintegrant can comprise up to about 20% by weight of the total composition and preferably from about 2 to about 10%.

In addition to the granules of this embodiment of the invention, the dosage form may include glidants, lubricants, binders, sweeteners, flavoring and coloring ingredients. Any conventional sweetening or flavoring ingredients may be used. Sweeteners, flavoring ingredients, or combinations of sweetening and flavoring ingredients can also be used.

Examples of useful binders include gum arabic, tragacanth, gelatin, starch, cellulosic materials such as methylcellulose and sodium carboxymethylcellulose, alginic acid and its salts, magnesium silicate, aluminum, polyethylene glycol , guar gum, polysaccharide acid, bentonite, sugar, invert sugar, etc. Binders may be used in amounts up to 60% and preferably from about 10 to about 40% by weight of the total composition.

Coloring agents may include titanium dioxide, and food suitable dyes such as those known as F.D.&C. dyes and natural colorants such as grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, red pepper color etc. Colorants may be used in amounts ranging from about 0.1% to about 3.5% by weight of the total composition.

Flavoring agents incorporated into the compositions may be selected from synthetic flavor oils and flavoring aromas and/or natural oils, extracts of plants, leaves, flowers, fruits, etc., and combinations thereof. These may include oils of cinnamon, wintergreen, peppermint, clove, cinnamon, anise, eucalyptus, thyme, cedar leaf, nutmeg, sage leaf, bitter almonds and cassia. Also useful as flavoring agents are vanilla, citrus oils including lemon, orange, grape, lime, and grapefruit, and fruit flavors including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot wait. Flavors that have been found to be particularly beneficial include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring agent used can depend on a number of factors, including the organoleptic effect desired. Flavoring agents may be present in an amount of from about 0.05 to about 3% by weight of the composition. Particularly preferred flavors are grape and cherry flavors and citrus flavors such as orange.

In one aspect the present invention provides a solid oral tablet dosage form suitable for sublingual administration. Excipient fillers may be used to aid in tableting. Ideally, the filler will also help the dosage form dissolve quickly in the mouth. Non-limiting examples of suitable fillers include: mannitol, dextrose, lactose, sucrose and calcium carbonate.

Tablets may be manufactured by direct compression, wet granulation or any other tablet manufacturing technique as described in US-A-6200604. Dosage forms may be administered to a human or other mammalian subject by placing the dosage form in the mouth of the subject and allowing it to remain in the mouth, under the tongue (sublingual administration). The dosage form naturally begins to disintegrate due to the moisture in the mouth. Disintegration, especially effervescence, can stimulate additional salivation, further enhancing disintegration.

While the formulations described above fall within the scope of the present invention, the most preferred orally dispersible solid pharmaceutical dosage form of the present invention comprises a pharmaceutically active peptide and an open matrix network carrying desmopressin composed of Inert water-soluble or water-dispersible carrier materials.

A pharmaceutical dosage form comprising an open matrix network is known from GB-A-1548022 with reference to its further detailed description. The pharmaceutical dosage form of the present invention is rapidly disintegrated by water. "Rapid disintegration" means that the shaped product disintegrates in water within 10 seconds. It is preferable that the shaped product disintegrates (dissolves or disperses) within 5 seconds or less. The disintegration time can be measured by a method similar to British Pharmacopoeia (1973), Disintegration Test for Tablets (B.P. 1973). This method is described in GB-A-1548022 and outlined below.

instrument

A glass or suitable plastic test tube 80-100mm long, about 28mm inside diameter, 30-31mm outside diameter, mounted at the lower end to form a basket, with a disc-shaped anti-rust gauze, meeting the requirements of a N.1.70 sieve.

The glass measuring cylinder has a flat bottom, an inner diameter of about 45mm, and contains water not less than 15cm deep at a temperature of 36-38°C.

Suspend the center of the basket in the graduated cylinder so that it can be raised and lowered repeatedly in a uniform manner so that at the highest point the gauze is just above the water and at the lowest point the upper edge of the basket is just enough to keep the water clear.

method

A shaped product is placed in the basket and it is raised and lowered in a manner that repeats a complete upward and downward motion at a rate of 30 times per minute. When no particles remain on the gauze, the shaped product disintegrates and the particles do not easily pass through the gauze. After 10 seconds no such particles will remain.

The term "open matrix network" refers to a network of water-soluble or water-dispersible carrier material having interstices dispersed throughout. The open matrix network of the carrier material is usually of low density. For example, the density may be within 10-200 mg/cc, such as 10-100 mg/cc, preferably 30-60 mg/cc. The density of the shaped product can be influenced by the amount of active ingredient or any other ingredient incorporated into the product and can be outside the above-mentioned preferred limits for matrix network density. The open matrix network, similar in structure to solid foam, allows liquids to enter the product through the voids and penetrate the interior. Penetration of the aqueous medium brings the carrier material inside and outside the product into contact with the action of the aqueous medium, whereby the network of carrier material rapidly disintegrates. The open matrix structure has a porous nature and improves product disintegration compared to common solid shaped pharmaceutical dosage forms such as tablets, pills, capsules, suppositories and pessaries. Rapid disintegration results in rapid release of the active ingredient carried by the matrix.

The carrier material used in the products of the present invention may be any water soluble or water dispersible material which is pharmacologically acceptable or chemically inert and which is capable of forming a rapidly disintegrating open matrix network. It is preferred to use a water soluble material as the carrier since this will allow the most rapid disintegration of the matrix when the product is placed in an aqueous medium. Particularly useful carriers may be formed from polypeptides such as gelatin, especially hydrolyzed gelatin, for example, gelatin hydrolyzed by heating in water. For example, gelatin can be partially hydrolyzed by heating an aqueous gelatin solution, 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. Hydrolyzed gelatin is preferably used at a concentration of about 1-6% w/v, most preferably 2-4%, eg about 3%.

While mammalian-derived gelatin can be used, it has an unpleasant taste and therefore requires the use of sweeteners and flavors to mask the taste of the active ingredient, in addition to any required to mask the taste of the active ingredient. The taste of gelatin. Furthermore, the heating step necessary to use mammalian gelatin increases processing time and entails heating costs, thereby increasing the overall cost of the process. Therefore, preference is given to using fish gelatin, especially non-gelling fish gelatin, especially for desmopressin. Reference is made to WO-A-0061117 for a further detailed description.

Instead of partially hydrolyzed gelatin or fish gelatin, other carrier materials can be used, for example polysaccharides such as hydrolyzed dextran, dextrin and alginates (e.g. sodium alginate) or mixtures of the above carriers with each other or with other carrier materials such as polyethylene Alcohol, polyvinylpyrrolidone or gum arabic. Modified starches may also be used instead of gelatin, as described in WO-A-0044351, to which reference is made for further details. Other carriers include water, lactose, starch, magnesium stearate, talc, vegetable oils, gums, alcohol, petrolatum (petrolatum), and the like.

The pharmaceutical dosage form according to the invention may be in the form of shaped products. They may incorporate other ingredients in addition to the active ingredient. For example, pharmaceutical dosage forms of the invention may incorporate pharmaceutically acceptable auxiliaries. Such adjuvants include, for example, coloring agents, flavoring agents, preservatives (eg, bacteriostatic agents) and the like. US-A-5188825 teaches that the water-soluble active agent should be bonded to the ion exchange resin to form a substantially water-insoluble active agent/resin complex; although this teaching can be practiced here (see US-A-5188825 for further details), However, it has been found in the development of the present invention that water-soluble peptides such as desmopressin can be formulated into solid dosage forms of the present invention without binding to ion exchange resins. Accordingly, such dosage forms may be free of ion exchange resins. In the case of hydrophobic peptides, desmopressin is not hydrophobic, a surfactant may be present, as taught in US-A-5827541, to which reference is made for further details. In the case of peptides with an unpleasant taste (desmopressin does not have this taste), lipids such as lecithin may be present to improve patient acceptability, as taught in US-A-6156339, reference further a detailed description of . Other strategies for taste masking include converting soluble salts to less soluble salts or to free base as taught in US-A-5738875 and US-A-5837287 and using the method disclosed in US-A-5976577 , wherein, prior to lyophilization, a suspension of uncoated or coated coarse particles of the pharmaceutically active substance in a carrier material is cooled in order to reduce the viscosity and to minimize the release of the active substance during processing, and to reduce the viscosity in excess of The form minimizes the unpleasant taste originating from the peptide at the point of disintegration in the oral cavity; reference is made to the cited patent for further details.

For insoluble or less soluble peptides with larger particle sizes, xanthan gum may be present, especially when the carrier is formed from gelatin, since xanthan gum acts as a flocculant for gelatin, as in US-A- 5631023, to which reference is made for further details.

When the matrix is selected from gelatin, pectin, soy fibrin and mixtures thereof, one or more amino acids having about 2 to 12 carbon atoms may be present as taught in WO-A-9323017. In such formulations, the preferred amino acid is glycine and the preferred matrix forming agents are gelatin and/or pectin; in a particularly preferred embodiment, the dosage form also comprises mannitol. All excipients should be chosen to be pharmaceutically acceptable.

The pharmaceutical dosage form of the present invention can be prepared by a method as described in GB-A-1548022, which includes sublimating a solvent in a composition comprising a solution of a drug and a carrier material dissolved in a solvent, the composition being in a mould. solid state.

Sublimation is preferably performed by freeze-drying a composition comprising a solution of the active ingredient and the carrier material in a solvent. The composition may include other ingredients, such as those mentioned above. The solvent is preferably water, but it may contain co-solvents such as alcohols such as tert-butanol to increase the solubility of the chemicals. The composition may also comprise a surfactant, such as Tween 80 (polyoxyethylene (20) sorbitan monooleate). Surfactants help prevent the freeze-dried product from sticking to the mold surface. It also aids in the dispersion of active ingredients.

The composition may contain a pH adjuster to adjust the pH of the solution used to prepare the dosage form, falling within the range of 3-6, preferably 3.5-5.5, and most preferably 4-5, eg 4.5-4.8. Citric acid is the preferred pH adjuster, but other acids including hydrochloric acid, malic acid may also be used. This non-volatile pH adjuster cannot be removed by lyophilization or other sublimation methods and therefore may be present in the final product.

The mold may include a series of cylindrical or other shaped depressions, each sized to correspond to the size of the desired shaped product. Alternatively, the size of the depression in the mold can be larger than the desired product size, and after the contents have been lyophilized, the product can be cut to the desired size (eg, thin discs).

However, as described in GB-A-2111423, the mold is preferably a depression in a sheet of film material. The film material may contain more than one depression. The film material may be similar to that used in conventional blister packs for packaging oral contraceptive tablets and similar drug forms. For example, the film material may be made of a thermoplastic material with depressions formed by thermoforming. A preferred film material is polyvinyl chloride film. Laminates of film materials may also be used.

In one embodiment, the mold comprises a metal plate (eg, an aluminum plate) containing one or more depressions. In a preferred method of using such molds, the mold is cooled with a cooling medium (eg, liquid nitrogen or solid carbon dioxide). While the mold is cooling, a predetermined amount of water containing the carrier material, active ingredient and any other desired ingredients is added to the depressions. When freezing the contents of the depression, the mold is depressurized and, if necessary, a controlled supply of heat is applied to aid sublimation. The pressure may be lower than about 4mmHg; GB-A-1548022 teaches the use of a pressure lower than 0.3mmHg, eg preferably 0.1-0.2mm. The lyophilized product can be removed from the recess of the mold and stored for future use, for example, in an airtight jar or other suitable storage container. Alternatively, the freeze-dried product may be sealed with a film material as described in GB-A-2111423.

A subsequently developed process for the preparation of pharmaceutical dosage forms according to the invention is described in GB-A-2111423, to which reference is made for further details. The method comprises filling a mold with a composition comprising a predetermined amount of active ingredient and a solution of partially hydrolyzed gelatin, passing a gaseous cooling medium through the mold, thereby freezing the composition in the mold, and then allowing solvent from the frozen composition sublimation, thereby producing a network of partially hydrolyzed gelatin carrying the active ingredient.

To help ensure a uniform thickness of the product, one or more side walls of the mold may diverge outwardly from the bottom and form an angle of at least 5 degrees from the vertical to the surface of the composition, as described in GB-A-2119246, Refer to its further detailed description.

Alternatively or additionally, the pharmaceutical dosage form of the present invention may be prepared by the method described in GB-A-2114440, which comprises freezing a composition comprising a water-soluble or water-dispersible carrier material inert to the active ingredient A solution in a first solvent which is sublimed from a frozen composition to produce a product having a network of carrier material to which a solution or mixture of a second non-aqueous solvent containing a predetermined amount of active ingredient is added suspension, and allow or cause the second solvent to evaporate. Reference is made to GB-A-2114440 for a further detailed description.

Alternatively or additionally, the pharmaceutical dosage form of the present invention may be prepared by the method described in GB-A-2111184, which comprises introducing a liquid medium in the form of droplets below the surface of a cooling liquid maintained at a temperature below the liquid At the temperature of the freezing point of the medium, the cooling liquid is immiscible with the liquid medium, is inert with respect to the liquid medium, and has a density greater than that of the liquid medium and the resulting frozen particles, such as liquid droplets floating towards their surface in the cooling liquid, they It is frozen to form spherical particles. The frozen spherical particles are collected at or near the upper surface of the cooling liquid. Reference is made to GB-A-2111184 for a further detailed description.

The bioavailability of the dosage forms of the present invention is improved. They can be taken orally and are well suited for this purpose. They disperse rapidly in the mouth, for example, by placing under the tongue (sublingual administration).

According to a second aspect of the present invention there is provided a dosage form as described above for use in medicine, in particular for delayed voiding, incontinence, primary nocturnal enuresis (PNE), nocturia and central diabetes insipidus.

The present invention provides a method for delaying excretion, treating or preventing incontinence, primary nocturnal enuresis (PNE), nocturia and/or central diabetes insipidus, the method comprising, for example, administering sublingually to a subject in the above-mentioned dosage form Potent and usually nontoxic amounts of desmopressin. Any other disease or condition treatable or preventable by desmopressin can be similarly treated using the present invention. The invention therefore extends to the use of desmopressin in the manufacture of a sublingual absorbable pharmaceutical formulation. The invention also extends to a package comprising a sublingual absorbable pharmaceutical dosage form of desmopressin and instructions for placing the dosage form under the tongue of a patient.

Also included in the invention are methods for preparing a packaged dosage form of desmopressin comprising combining a sublingual absorbable pharmaceutical dosage form of desmopressin with instructions for placing the dosage form under the tongue of a patient. For example, when selling or dispensing, instructions may be printed on the package containing the dosage form, or may be printed on a product information leaflet or inserted into the package.

In addition to desmopressin, other peptides may be formulated in the formulations described above. The invention therefore extends to pharmaceutical dosage forms of pharmaceutically active peptides suitable for oral absorption.

According to yet another aspect of the present invention, there is provided a solid pharmaceutical dosage form, e.g. for oral administration, comprising a pharmaceutically active peptide and an open matrix network carrying the peptide, the open matrix network being composed of a water-soluble compound inert to the peptide. or water-dispersible carrier material.

Although oral vaccines made from fast dissolving forms are known from WO-A-9921579, no pharmaceutically active peptides have been disclosed which retain their activity after administration. The experimental work in WO-A-9921579 only shows the presence of IgA antibodies against tetanus toxoid in saliva after administration of tetanus toxoid with a vaccine formulation adjuvanted with fast dissolving administration. The formulations of the invention are not vaccines and do not include adjuvants.

The pharmaceutical dosage form of this aspect of the invention comprises a pharmaceutically active peptide. Such peptides may be active themselves directly, or they may have one or more active metabolites, ie they may be prodrugs of the main or true active ingredient. The peptide may have, for example, 2-20, preferably 5-15 amino acid residues (at least some of which may be the D-isomer, although the L-isomer will usually predominate). The peptide may be linear, branched or cyclic, and may include natural residues or substituents or residues or substituents that are commonly or not found in native peptides or proteins. Pharmaceutically acceptable salts, simple adducts and tautomers may be included as desired.

Examples of peptides usefully formulated using the present invention include somatostatin and its analogs, including cyclic (MeAla-Tyr- _D -Trp-Lys-Val-Phe) and cyclic (Asn-Phe-Phe- _D -Trp- _D- Lys-Thr-Phe-GABA), enkephalins including Met ⁵ -enkephalin and Leu ⁵ -enkephalin, oxytocin analogues such as atosiban (1-deamino-2- _D -Tyr-( OEt)-4-Thr-8-Om-Oxytocin), GnRH analogues such as triptorelin (6- _D -Trp-GnRH), lipuan ([ _D -Leu ⁶ , Pro ⁸ -NHEt]-GnRH ), degarelix (Ac- _D -2Nal- _D -4Cpa- _D -3Pal-Ser-4Aph (L-hydrogenated orotic acid) _-D -4Aph(Cbm)-Leu-Ilys-Pro- _D- Ala-NH ₂ , Wherein 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pa l is 3-pyridylalanine, Ilys is N(8)-isopropyllysine, 4Aph is 4- aminophenylalanine and Cbm is carbamoyl) and other GnRH antagonists disclosed in US-A-5925730 and US-A-4072668, as well as vasopressin analogs such as desmopressin. It is especially preferred to utilize the present invention to formulate agonists of naturally active peptides, such as those described above, because agonists can be active at lower doses than antagonists.

The dosage will be determined by the attending physician or clinician, 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 a peptide in the manufacture of a dosage form as described above for the treatment or prevention of a disease or condition treatable or preventable by the peptide.

The present invention also provides a method of preventing a disease or condition treatable or preventable by a peptide, the method comprising administering to a subject an effective and generally non-toxic amount of the peptide in the above-described dosage form.

Low Dose Analysis and Applications

As indicated above, doses and plasma/plasma/serum concentrations of desmopressin that are 5-40% of the currently recommended doses and resulting plasma/plasma/serum levels are therapeutically effective and, in some cases, for specific diseases such as Safer for CDI, PNE, and other clinical indications that require pharmacologically concentrated urine.

Clinical observations of the use of desmopressin in adult men and women for the treatment of a condition known as nocturia (which results in frequent nocturnal urination) suggest that lower doses of desmopressin are advisable. In this patient population, standard intranasal and oral doses of desmopressin produced an unexpectedly high incidence of hyponatremia, a condition in which plasma/plasma/serum sodium falls to abnormally low levels. Hyponatremia can lead to seizures, irregular heartbeat, cerebral edema, and death. The oral dose of desmopressin is 100-400mcg and the intranasal dose is 10-20mcg. Although these doses reduced the incidence of nocturia, hyponatremia indicated that the dose was unnecessarily high, resulting in prolonged pharmacodynamic effects on urine concentrations followed by hyperhydration and plasma/plasma/serum sodium Reduced dilution. Lower doses of desmopressin will produce adequate but not excessive urinary suppression in terms of magnitude and duration of action.

According to the present invention, the plasma/plasma/serum desmopressin concentration after administration of the pharmaceutical composition of the present invention is preferably about 0.1 pg/mL to about 10.0 pg/mL, and more preferably about 0.5 pg/mL to about 5.0 pg/mL . Desmopressin in these amounts and ranges can be administered by any method known in the art, including, but not limited to, intravenous (bolus injection, infusion); subcutaneous (bolus injection, infusion); injection, long-acting); intranasal; transmucosal (oral and sublingual, e.g., orally dispersible tablets, discs, films, and effervescent formulations; conjunctival (eye drops); rectal (suppositories, enemas) )); transdermal (passive absorption via patch, gel, cream, ointment, or iontophoresis); or intradermal (bolus injection, infusion, long-acting). In addition, pharmaceutical compositions containing desmopressin in an amount to provide the plasma/plasma/serum desmopressin levels described above can be prepared by the methods described above and using the carriers described above, or any other method known in the art.

The dose ranges for desmopressin listed above produce suitable urinary diuretics when administered by the various routes outlined in the following examples:

Administration of low-dose desmopressin can be an effective treatment option for clinical indications such as treatment of central diabetes insipidus, prevention of primary nocturnal enuresis, prevention of nocturia, treatment of clinical conditions associated with nocturia, including but not limited to Sleep disturbances, prevention of incontinence (stress response, impulsiveness, etc.), and delayed voiding during waking hours.

Specific formulations of desmopressin can also be manufactured that enhance absorption and increase its systemic bioavailability. These formulations may result in increased pharmacological effects at various points along the dose-response curve, thereby enhancing the activity of even lower doses of desmopressin.

Detailed ways

The present invention is described in further detail by the following examples. All parts and percentages are by weight unless expressly stated otherwise.

Example 1 Orodispersible dosage form of 200 μg desmopressin

Spray-dried fish gelatin (4 g) and mannitol (3 g) were added to a glass beaker. Purified water (93 g) was then added and the solution was stirred using a magnetic follower. Check the pH and adjust to 4.8 with citric acid if necessary. A Gilson pipette can then be used to deliver 500 mg of this solution into a series of pre-formed individual blister wells having a well diameter of approximately 16 mm. The blister laminate may comprise PVdC coated PVC. The dosing unit was then frozen in a freezing tunnel at -110°C for a residence time of 3.2 minutes, and then placed in an upright freezer at -25°C (±5°C) for more than 1.5 hours. The units were then lyophilized overnight at a pressure of 0.5 mbar with an initial storage temperature of 10°C raised to +20°C. The unit can be checked for moisture by drying the trace and passing a pressurized moisture check before removing the load.

In this manner, orally dispersible dosage forms of desmopressin were prepared following the general procedure given in Example 1 of WO-A-0061117 using the following ingredients per unit dosage form:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg

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

Fish Gelatin USNF/EP 20mg

Citric acid (if needed) (pH adjuster) qs, to pH 4.8

Purified Water (removed during processing)

Example 2 Orodispersible dosage form of 400 μg desmopressin

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

Example 3 Orodispersible dosage form of 800 μg desmopressin

The procedure of Example 1 herein was followed except that the amount of desmopressin per unit dosage form was 800 [mu]g.

Example 4 Orodispersible dosage form of 200 μg desmopressin

Following the general procedure given in Example 1 of WO-A-0061117, orally dispersible dosage forms of desmopressin were prepared using the following ingredients per unit dosage form:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg

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

Fish Gelatin USNF/EP 10mg

Citric acid (if needed) (pH adjuster) qs, to pH 4.8

Purified Water (Removed During Processing)

Example 5 Orodispersible dosage form of 400 μg desmopressin

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

Example 6 Orodispersible dosage form of 800 μg desmopressin

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

The iv solution of comparative example 1 desmopressin

Injectable formulations of desmopressin are conventionally prepared using the following ingredients:

Desmopressin (PolyPeptide Laboratories, Sweden) 4mg

Sodium chloride 9mg

(National Corporation of Swedish

Pharmacies, Sweden)

Hydrochloric acid (1N) (Merck, Germany) qs, to pH 4

Water for Injection Appropriate amount, up to 1ml

Comparative Example 2 Conventional tablet of 200 μg desmopressin

Using conventional wet granulation procedures, tablets were prepared containing the following ingredients:

Desmopressin (PolyPeptide Laboratories, Sweden) 200 μg

Lactose (Pharma tose 150M, DMV, The Netherlands) 120mg

Potato starch (Lyckeby AB, Sweden) 77mg

PVP (Kollidon 25, BASF, Germany) 1.8mg

Magnesium stearate (Peter Greven, Germany) 1 mg

Granulation liquid (water, ethanol) (removed during processing)

Comparative Example 3 Conventional tablet of 100 μg desmopressin

The process of Comparative Example 2 was carried out, except that the amount of desmopressin per tablet was 100 μg.

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

Research design

24 healthy non-smoking male volunteers participated in this study. The study was designed as a central, open-label, randomized, balanced four-way crossover phase I study. In random order, each subject was given 200 μg, 400 μg and 800 μg of orodispersible desmopressin sublingually (Examples 4, 5 and 6, respectively) and 2 μg by i.v. bolus injection (Comparative Example 1). There was a 72-hour washout period between doses. In order to normalize the oral mucosa prior to administration of the orodispersible tablet, the subjects were asked to refrain from eating, chewing gum, etc. Before dosing, subjects were asked to brush their teeth in the morning without toothpaste.

blood sample

Blood samples were collected and plasma concentrations of desmopressin were measured on the following schedule: pre-dose and 15, 30 and 45 minutes post-dose and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours. Following intravenous dosing, additional blood samples were collected at 5 and 10 minutes post-dose.

Assay

Desmopressin concentrations in plasma were determined by a validated RIA method.

Pharmacokinetic Analysis

Using the commercially available software WillNonlin ^™ Pro, ver. 3.2 (Pharsight Corporation, US), the desmopressin concentration in the plasma of each volunteer in each administration group was analyzed by a non-compartmental method. Plasma concentration values below the limit of measurement (LOQ) followed by values above the LOQ were set as 'LOQ/2' for NCA analysis and descriptive statistics for concentrations. Values below the LOQ, but then not above the LOQ were excluded from the NCA analysis and were set to zero in the descriptive statistics for concentrations.

Pharmacokinetic analysis results

After iv administration, the mean volume of distribution (Vss) at steady state was 29.7 dm ³ . The calculated average clearance rate was 8.5 dm ³ /hr and the measured average elimination half-life was 2.8 hours. Following oral administration of desmopressin, maximum plasma concentrations are observed 0.5-2.0 hours post-dose. After oral administration of 200, 400 and 800 μg, the maximum plasma concentrations were 14.25, 30.21 and 65.25 pg/ml, respectively. After reaching a maximum, desmopressin is eliminated with a mean elimination half-life of 2.8-3.0 hours. The bioavailability was determined to be 0.30%, with a 95% confidence interval of 0.23-0.38%.

The pharmacokinetics of desmopressin were linear when the orodispersible dosage forms of Examples 4, 5 or 6 were administered.

Comparative Example 4 Bioavailability of desmopressin administered according to Comparative Examples 2 and 3

Thirty-six healthy male volunteers (Caucasian, Black and Hispanic) participated in this study, which was designed as an open-label, single-dose, three-way crossover study. In random order, each subject was administered 200 μg of desmopressin in the form of a single 200 μg tablet (Comparative Example 2), 200 μg of desmopressin in the form of two 100 μg tablets (Comparative Example 3), And 2 μg of desmopressin was administered in the form of i.v. bolus injection administration (comparative example 1).

After i.v. administration, the mean elimination half-life was determined to be 2.24 hours. Following oral administration of desmopressin, maximum plasma concentrations were observed at 1.06 hours (2 x 100 μg) or 1.05 hours (1 x 200 μg) post-dose. After oral administration of 2x100μg and 1x200μg, the maximum plasma concentrations were 13.2 and 15.0pg/ml, respectively. The bioavailability was determined to be 0.13% (2x100μg) or 0.16% (1x 200μg).

Example 8 : A Crossover Study of Three Low-Dose Desmopressin's Urinary Effects

The studies described in the following Examples demonstrate the urinary-inhibitory effect of three low doses of desmopressin administered via a 2-hour intravenous infusion in hyperhydrated, healthy, nonsmoking male and female volunteers. Briefly, 8 healthy, hyperhydrated, nonsmoking male and female volunteers aged 18-40 years were included in an open-label crossover study. Subjects were dosed at an initial 0.5 ng/kg dose, then a 1.0 ng/kg dose, and finally a 2.0 ng/kg dose. Pharmacodynamic and pharmacokinetic parameters were evaluated at each dose level. A two-day (48 hour) washout period was observed between doses.

Eight subjects, 5 males and 3 females, were evaluated in this study. Their weights expressed in kilograms were 85.9, 65, 80.9, 63.3, 72.5, 67.6, 63.5, and 54.5. The average weight of the eight subjects was 69.15 kg, which was very close to the standard weight estimate of 70 kg. The dose and blood levels of vasopressin are based on it. Subjects were hyperhydrated by drinking water equal to 1.5% body weight on Study Day 1 (dose first day) and maintained by water intake to replace urine excretion. Desmopressin at 0.5, 1.0 and 2.0 ng/kg in 100 mL sterile saline (0.9%), USP for injection was used in the study. On days 1, 3, and 5 of the study, 3 desmopressin infusions (one of each concentration above) were given at constant rate I.V. infusions every 2 hours. Each subject remained in the clinic for a period of 7 days from 1 day before the first dose to 1 day after the last dose. The first dose was 0.5ng/kg. After the end of the desmopressin infusion, the subject excreted and monitored every 20 minutes until the urine output level exceeding 10 mL/min was collected for 3 consecutive measurements. At this point, hyperhydration ceases. Urine osmolality was measured 20 minutes before the infusion, at baseline, and every 20 minutes until 6 hours after the start of the infusion. Urine specific gravity was also measured. Plasma/serum sodium and plasma/serum osmolality were measured prior to dosing and at 2, 4, and 6 hours after initiation of the infusion. Blood samples for pharmacokinetic determinations were collected prior to dosing, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the start of the infusion. This same procedure was followed for 1.0 ng/kg and 2.0 ng/kg infusions. On Day 6, approximately 24 hours after the third and final desmopressin infusion, subjects were withdrawn for a physical examination including laboratory evaluation of vital signs, blood and urine.

Evaluation criteria for this study included urine output over time, urine osmolality over time, urine specific gravity over time, and plasma/plasma/serum osmolality and sodium over time. Statistical analysis was performed on the above criteria. The statistical analysis was descriptive and all statistical hypothesis testing was performed for exploratory purposes. The following studies were performed: Duration of action was estimated for each subject using 3 different levels of osmolality (150mOsm/kg, 200mOsm/kg and 400mOsm/kg) as breaks, i.e., from 'Onset' to 'Onset'end' time. First, duration of action was defined as from onset of action (i.e., the first time after dosing in which the urine osmolality was below 150 mO sm/kg) to end of action (the first subsequent time in which the urine Osmolality below 150 mO sm/kg and confirmed at the next time interval unless the first subsequent time is the time of the last observation point). The second and third estimates used 200mOsm/kg and 400mOsm/kg as cutoff levels for the 'start' and 'end' of the effect, respectively. Subjects whose effects were not 'over' by definition were examined when urine output returned to baseline (over 10 mL/min) and/or when the process of hyperhydration was terminated. The overall duration of action for each dose group was estimated using the nonparametric Kaplan-Meier method. Different methods of estimating the duration of action are expected to give lower and upper bounds on the true probability, ie, the probability of desmopressin activity as a function of time. In addition, the duration of action for each treatment group is given using mean, SD, median, minimum and maximum values. The dose-response relationship between duration of action and dose is investigated using an appropriate linear or nonlinear model. The pharmacokinetic parameters are derived from the desmopressin concentration vs. time curves, namely AUC (area under the plasma concentration-time curve up to infinity), C _max (maximum observed plasma concentration), t _max (after administration _Cmax ), CL (total systemic clearance), _Vz (volume of distribution in the terminal phase), _AUCt (area under the plasma concentration-time curve from time 0 to time t), _λz (vs. The terminal (log-linear) portion of the plasma concentration-time curve estimated by linear regression of the logarithm of concentration is related to the first-order rate constant) and t _1/2 (terminal half-life).

Summary of results:

All three doses (I.V. infusion) of desmopressin produced measurable diuresis in a dose-response fashion, with increases in urine concentration (osmolality) and decreases in urine output. The duration of action of the diuretic effect also confirmed that the dose-response curve of the lowest dose had the shortest duration of action. Mean peak urine osmolality (mOsm/kg) for each dose level occurred at the end of the 2-hour infusion. Baseline mean urine osmolality was 55.8, 55.8, and 55.6 mOsm/kg for the 0.5, 1.0, and 2.0 ng/kg doses, respectively. The mean peak urine osmolality at 2 hours for the 0.5, 1.0, and 2.0 ng/kg doses was 206.0, 444.7, and 587.2 mOsm/kg, respectively. The mean minimum urine output (mL/min) for each dose level also occurred at the end of the 2-hour infusion. Baseline mean urine output was 18.6, 16.6, and 16.9 mL/min for the 0.5, 1.0, and 2.0 ng/kg doses, respectively. The mean minimum voided volumes were 7.1, 1.3 and 0.7 mL/min for the 0.5, 1.0 and 2.0 ng/kg doses, respectively. The duration of diuresis was about 180 minutes for the 0.5 ng/kg dose, 240-280 minutes for the 1.0 ng/kg dose and 360 minutes for the 2.0 ng/kg dose. The urine osmolality and urine output results for each subject and the mean values for each time period are described in Tables 1-6 and Figures 1-9.

As shown in Tables 1-6 and Figures 1-9, low-dose desmopressin administered by I.V. infusion produced significant inhibitory effects in hyperhydrated normal subjects in a dose-response manner within 2 hours. urine effect. These desmopressin doses and calculated plasma/serum concentrations are well below current label recommendations and current clinical practice by more than an order of magnitude. The pharmacodynamic duration of action was also dose proportional, with the 1.0 and 2.0 ng/kg doses providing a duration of 4-6 hours. This is sufficient to allow desmopressin to have the desired therapeutic effect for existing and potential new clinical indications. Safety and tolerability were excellent.

The findings confirm the low-dose hypothesis for desmopressin and provide the basis for further clinical studies in patients evaluating low-dose desmopressin in patients with conditions such as primary nocturnal enuresis, adult nocturia, incontinence, and central diabetes insipidus. The role of other diseases provides an empirical basis.

The therapeutic effectiveness of desmopressin for all these clinical indications is based on desmopressin's urostatic pharmacology, which results in the production of smaller volumes of more concentrated urine. In people with central diabetes insipidus, the pituitary gland produces little or no vasopressin, the natural urostatic hormone. This deficiency results in the production of large volumes of very dilute urine, which can lead to dehydration and severe metabolic abnormalities unless the patient drinks very large amounts of water. Desmopressin replaces deficient vasopressin and restores normal urine concentration and volume in these patients. In patients with primary nocturnal enuresis (bedwetting), the diuretic effect of desmopressin reduces the volume of urine at night, reducing the amount of urine that the bladder must retain and thereby reducing or eliminating the occurrence of enuresis.

In adults with nocturia, there is nocturnal polycoma (production of large volumes of urine), low bladder capacity, or increased bladder sensitivity to urine volume. In all these cases, the bladder's threshold for retaining urine at night is often exceeded several times, leading to a neural signal for voiding. The patient is thus awakened for voiding. The diuretic effect of desmopressin reduces nocturnal urine production, delays the time to exceed the excretion threshold, allows longer sleep before voiding and reduces the number of nocturnal voids.

In patients with various types of incontinence (stress, impulsivity, etc.) often associated with bladder abnormalities due to surgery, childbirth, and aging, the bladder is unable to hold even normal volumes of urine. The volume threshold for voiding is low and the risk of involuntary voiding (incontinence) is high. The diuretic effect of desmopressin reduces urine production, delaying excretion because, in these patients, there is a delay in exceeding the abnormally low volume threshold for excretion.

In all of the above clinical indications, or medical use of desmopressin, its urostatic pharmacological action leading to a reduction in the production of more concentrated urine is the mechanism of therapeutic effectiveness. This clinical study demonstrates that desmopressin produces this major anti-uria effect at lower doses and lower blood concentrations than previously thought. Therefore, lower doses and concentrations of desmopressin can be used to treat patients with all of the above conditions.

The present invention relates to the following embodiments:

Embodiment 1. A pharmaceutical composition comprising 0.5ng-20μg desmopressin and a pharmaceutically acceptable carrier.

Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises from about 0.5 ng to about 2000 ng of desmopressin.

Embodiment 3. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises from about 0.05 μg to about 10 μg desmopressin.

Embodiment 4. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition comprises from about 0.1 μg to about 20 μg desmopressin.

Embodiment 5. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is suitable for intravenous, subcutaneous, transmucosal, transdermal, or intradermal delivery.

Embodiment 6. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is in the form of an orally dispersible solid.

Embodiment 7. The pharmaceutical composition of embodiment 1, further comprising an open matrix network comprising a water-soluble or water-dispersible carrier material that is inert to desmopressin.

Embodiment 8. A pharmaceutical composition comprising desmopressin and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is effective to establish from about 0.1 picograms desmopressin/mL plasma/serum to about 10.0 picograms Steady plasma/serum desmopressin concentration in grams desmopressin/mL plasma/serum.

Embodiment 9. The pharmaceutical composition of embodiment 8, wherein the stable plasma/serum desmopressin concentration is from about 0.5 picograms desmopressin/mL plasma/serum to about 5.0 picograms desmopressin Vein/mL plasma/serum.

Embodiment 10. The pharmaceutical composition of embodiment 8, wherein the pharmaceutical composition comprises from about 0.5 ng to about 2000 ng of desmopressin.

Embodiment 11. The pharmaceutical composition of embodiment 8, wherein the pharmaceutical composition comprises from about 0.05 μg to about 10 μg desmopressin.

Embodiment 12. The pharmaceutical composition of embodiment 8, wherein the pharmaceutical composition comprises from about 0.1 μg to about 20 μg desmopressin.

Embodiment 13. The pharmaceutical composition of embodiment 8, wherein the pharmaceutical composition is suitable for intravenous, subcutaneous, transmucosal, transdermal, or intradermal delivery.

Embodiment 14. An article of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said pharmaceutical composition is therapeutically effective for the treatment or prevention of hemophilia, von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, and wherein the packaging material includes instructions for explaining that the pharmaceutical composition can be used for the treatment or prevention of hemophilia, von Willebe Labeling for Lande's disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, and wherein the pharmaceutical composition comprises 0.5ng-20μg desmopressin and a pharmaceutically acceptable carrier.

Embodiment 15. A method of treating or preventing a disease or condition treatable or preventable by desmopressin, said method comprising administering to a patient a daily dose of a therapeutically effective amount comprising 0.5 ng-20 μg of desmopressin and a pharmaceutical A pharmaceutical composition with an acceptable carrier.

Embodiment 16. The method of embodiment 15, wherein the disease or condition is selected from hemophilia, von Willebrand's disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus .

Embodiment 17. A method of inducing antiuria in a patient comprising the step of administering to the patient a daily dose of a therapeutically effective amount of a pharmaceutical composition comprising 0.5 ng-20 μg of desmopressin and a pharmaceutically acceptable carrier.

Embodiment 18. The method of embodiment 17, wherein the patient suffers from a disease selected from von Willebrand's disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus.

Claims (20)

1. pharmaceutical composition that comprises 0.5ng-20 μ g Desmopressin and pharmaceutical acceptable carrier, wherein said pharmaceutical composition can be set up the stable plasma Desmopressin concentration of about 0.1 microgamma Desmopressin/mL plasma to about 10.0 microgammas Desmopressin/mL plasma.

2. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises the about 10 μ g Desmopressins of about 0.05 μ g-.

3. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises the about 2 μ g Desmopressins of about 0.1 μ g-.

4. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition is suitable for intravenous, subcutaneous, saturating mucosa, percutaneous or Intradermal and sends.

5. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition is the form of oral cavity dispersible solid.

6. the pharmaceutical composition of claim 1 also comprises open substrate net, and described open substrate net comprises Desmopressin is inert water solublity or water dispersible carrier material.

7. the pharmaceutical composition of claim 1, wherein said stable plasma Desmopressin concentration are that about 0.5 microgamma Desmopressin/mL plasma is to about 5.0 microgammas Desmopressin/mL plasma.

8. one kind comprises packaging material and is included in manufacturing a product of the interior pharmaceutical composition of described packaging material, wherein said pharmaceutical composition can be treated and is used for the treatment of effectively or prevent hemophilia, Feng's von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, and wherein said packaging material comprise be used to illustrate this pharmaceutical composition can be used for the treatment or the prevention hemophilia, Feng's von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or the label of central diabetes insipidus, and wherein said pharmaceutical composition comprises 0.5ng-20 μ g Desmopressin and pharmaceutical acceptable carrier, and wherein said pharmaceutical composition can be set up the stable plasma Desmopressin concentration of about 0.1 microgamma Desmopressin/mL plasma to about 10.0 microgammas Desmopressin/mL plasma.

9. treat or prevent and to treat or the disease of prevention or the method for disease by Desmopressin for one kind, described method comprises and gives the pharmaceutical composition that the patient comprises 0.5ng-20 μ g Desmopressin and pharmaceutical acceptable carrier that described pharmaceutical composition can be set up the stable plasma Desmopressin concentration of about 0.1 microgamma Desmopressin/mL plasma to about 10.0 microgammas Desmopressin/mL plasma.

10. the method for claim 9, wherein said disease or disease are selected from hemophilia, Feng's von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia or central diabetes insipidus.

11. the method for claim 9, wherein said pharmaceutical composition comprise the about 10 μ g Desmopressins of about 0.05 μ g-.

12. the method for claim 9, wherein said pharmaceutical composition comprise the about 2 μ g Desmopressins of about 0.1 μ g-.

13. being suitable for intravenous, subcutaneous, saturating mucosa, percutaneous or Intradermal, the method for claim 9, wherein said pharmaceutical composition send.

14. the method for claim 9, wherein said stable plasma Desmopressin concentration are that about 0.5 microgamma Desmopressin/mL plasma is to about 5.0 microgammas Desmopressin/mL plasma.

15. method of in the patient, inducing the Urina Hominis (processed) effect, comprise giving the step that the patient comprises the pharmaceutical composition of 0.5ng-20 μ g Desmopressin and pharmaceutical acceptable carrier that described pharmaceutical composition can be set up the stable plasma Desmopressin concentration of about 0.1 microgamma Desmopressin/mL plasma to about 10.0 microgammas Desmopressin/mL plasma in described patient.

16. the method for claim 15, wherein said patient suffers from the disease that is selected from Feng's von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia or central diabetes insipidus.

17. the method for claim 15, wherein said pharmaceutical composition comprise the about 10 μ g Desmopressins of about 0.05 μ g-.

18. the method for claim 15, wherein said pharmaceutical composition comprise the about 2 μ g Desmopressins of about 0.1 μ g-.

19. being suitable for intravenous, subcutaneous, saturating mucosa, percutaneous or Intradermal, the method for claim 15, wherein said pharmaceutical composition send.

20. the method for claim 15, wherein said stable plasma Desmopressin concentration are that about 0.5 microgamma Desmopressin/mL plasma is to about 5.0 microgammas Desmopressin/mL plasma.

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