JP2016026200A - Pharmaceutical compositions comprising low dosages of desmopressin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide pharmaceutical compositions comprising low dosages of desmopressin.SOLUTION: A pharmaceutical composition for use in treatment or prevention of incontinence or for inducing voiding postponement comprises desmopressin and a pharmaceutically acceptable carrier in a dosed unit of 0.5 ng to 2000 ng desmopressin dosed by intranasal administration.SELECTED DRAWING: None

Description

  The present invention relates to pharmaceutical compositions containing desmopressin, and more particularly to pharmaceutical compositions containing low doses of desmopressin for treating certain human diseases.

  Desmopressin (1-desamino-8-D-arginine vasopressin, dDAVP) is an analog of vasopressin. Desmopressin has lower pressor activity and higher antidiuretic activity than vasopressin. This pharmacological profile allows desmopressin to be used clinically as an antidiuretic that does not cause a significant increase in blood pressure. Desmopressin is commercially available in tablet form as acetate and as a nasal spray and, among other indications, includes micturition delay, incontinence, primary nocturnal enuresis (PNE), including central diabetes insipidus. ) And nocturia are commonly prescribed.

  Desmopressin is administered intravenously, subcutaneously, intranasally and orally. Intravenous route administration is used almost exclusively in treating patients with mild hemophilia or von Willebrand disease to increase blood levels of factor VIII before surgery in the clinic. Subcutaneous injection is rarely and primarily used in patients with vasopressin deficiency, which results in the production of large amounts of extremely thin urine in the kidneys that can cause central diabetes insipidus, severe dehydration. Intranasal administration of desmopressin by nasal spray is approved for maintenance treatment of patients with central diabetes insipidus and children with primary nocturnal enuresis (age 6-12 years). In addition, desmopressin in an oral tablet form is approved for the treatment of central diabetes insipidus and primary nocturnal enuresis.

Today, approved labels for desmopressin recommend administration in the following ranges, depending on clinical signs and route of administration.

  The maximum plasma / plasma / serum concentration achieved with a typical intranasal dose consisting of 20 micrograms (mcg or μg) desmopressin for CDI or PNE is about 20 based on 3-5% bioavailability. Will be -30 pg / mL. For desmopressin oral tablets with a bioavailability of only 0.1-0.15%, standard 200-400 mcg doses still show peak plasma / plasma / serum levels of 20-30 pg / mL. I will.

Fjellestad-Paulsen A.M. Et al., Clin. Endocrinol. 38, 177-82 (1993)

  Existing desmopressin formulations meet patient needs, but still need improvement. Tablets are often preferred by patients because of their use, ease of differentiation, and lack of doubt about correct administration. However, tablets generally need to be taken with a glass of water or other beverage, which is problematic because liquid intake needs to be limited in connection with desmopressin treatment, and The message to the patient is clearer when there is no water intake. Furthermore, while the above doses and plasma / plasma / serum concentrations are effective for treating CDI and PNE, standard desmopressin doses cause undesirable side effects including high incidence of hyponatremia I know that. Lower doses are preferred if they can produce the same desired effect. However, recent trends in this area are evaluating higher doses of desmopressin for therapeutic purposes.

  In one aspect, the invention is directed to a pharmaceutical composition comprising 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier.

  In other embodiments, the invention includes desmopressin and a pharmaceutically acceptable carrier, and ranges from about 0.1 picogram desmopressin per mL plasma / plasma / serum to about 10.0 picogram desmopressin per mL plasma / plasma / serum. It is directed to pharmaceutical compositions that are effective in establishing steady-state plasma / plasma / serum desmopressin concentrations.

  In another aspect, the present invention is directed to a product comprising a packaging material and a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition comprises hemophilia, von Willebrand disease, incontinence, primary Therapeutically effective to treat or prevent nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, the packaging material having a pharmaceutical composition of hemophilia, von Willebrand disease, Including a label indicating that it can be used to treat or prevent incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, the pharmaceutical composition comprising 0.5 ng to Contains 20 μg desmopressin and a pharmaceutically acceptable carrier.

  In another aspect, the invention is directed to a method of treating or preventing a disease or condition treatable or preventable by desmopressin, said method comprising 0.5 ng to 20 μg desmopressin and a pharmaceutically acceptable for a patient. Administering a daily dose of a therapeutically effective amount of a pharmaceutical composition comprising a carrier.

  In another aspect, the invention comprises administering to a patient a daily dose of a therapeutically effective amount of a pharmaceutical composition containing 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier. Targeting methods to induce antidiuretic effects in patients

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

That is, the gist of the present invention is as follows.
[1] Use of desmopressin and a pharmaceutically acceptable carrier in a dosage unit for administering 0.5 ng to 2000 ng of desmopressin by intranasal administration, for use in the treatment or prevention of urinary incontinence, or to delay urination A pharmaceutical composition for inducing,
[2] Establish steady plasma / serum desmopressin concentrations ranging from 0.1 picogram desmopressin per ml plasma / serum to a maximum of 10.0 picogram desmopressin per ml plasma / serum when administered to a patient. Including 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier configured for intranasal, sublingual, buccal, transmucosal, transdermal, or intradermal administration A pharmaceutical composition for the treatment or prevention of urinary incontinence or for inducing urination delay,
[3] The pharmaceutical composition according to [2], comprising 0.5 ng to 10 μg of desmopressin,
[4] The pharmaceutical composition according to [2], comprising 0.5 ng to 2000 ng of desmopressin,
[5] Establish steady plasma / serum desmopressin concentrations from 0.5 picogram desmopressin per ml plasma / serum to 5.0 picogram desmopressin per ml plasma / serum when administered to a patient, [2] To [4] any one of the pharmaceutical compositions,
[6] Use of desmopressin and a pharmaceutically acceptable carrier in a dosage unit for administering 0.5 ng to 600 μg of desmopressin by intranasal administration, for use in the treatment or prevention of urinary incontinence, or to postpone urination It relates to a pharmaceutical composition for inducing.

  The present invention can provide a pharmaceutical composition containing a low dose desmopressin.

The present invention will be more fully understood by combining the above detailed description with the accompanying drawings.
It is a figure which shows the urine osmolality osmolality of each object obtained by 0.5 ng / kg desmopressin administration. It is a figure which shows the urine osmolality of each subject obtained by 1.0ng / kg desmopressin administration. It is a figure which shows the urine osmolality osmolality of each object obtained by 2.0 ng / kg desmopressin administration. It is a figure which shows the urinary excretion amount of each subject obtained by 0.5 ng / kg desmopressin administration. It is a figure which shows the amount of urine excretion of each subject obtained by 1.0ng / kg desmopressin administration. It is a figure which shows the amount of urinary excretion of each object obtained by 2.0ng / kg desmopressin administration. It is a figure which shows the average urine osmolality obtained by 0.5, 1.0, and 2.0 ng / kg desmopressin administration. It is a figure which shows the average urinary excretion amount obtained by 0.5, 1.0, and 2.0 ng / kg desmopressin administration. It is a figure which shows the average urine osmolality and the average urinary excretion obtained by 0.5, 1.0, and 2.0 ng / kg desmopressin administration.

  It has now been discovered that desmopressin can be administered as a solid dosage form that is absorbed through the mouth and provides enhanced bioavailability. Available evidence indicates that desmopressin administered intraorally (sublingually) is not significantly absorbed (Fjellestad-Paulsen A. et al., Clin. Endocrinol. 38, 177- 82 (1993)), it is surprising that desmopressin can really be absorbed in this way. It is even more unexpected that bioavailability can be improved compared to conventional oral tablet formulations (ie, formulations that are swallowed by patients).

  It has also been unexpectedly discovered that low doses of desmopressin and plasma / plasma / serum levels are pharmacologically active and can achieve the desired maximum therapeutic efficacy. The inventor believes that the currently recommended dosage and desmopressin dosage and plasma / plasma / serum concentrations that are 5-40% of the resulting plasma / plasma / serum levels are therapeutically effective. It has been found that in some cases it is safer for the treatment of further clinical signs that require pharmacological enrichment of CDI, PNE, and urine. The actual dose-response curve of desmopressin shifts to the left compared to current theory and practice, and the pharmacological effects on urine concentration at each plasma / plasma / serum concentration point over the expected dosage range It has been discovered that an increase in is observed.

  According to a first aspect of the present invention, there is provided a pharmaceutical dosage form configured for sublingual absorption of desmopressin.

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

  The formulation is typically a solid. It can disperse rapidly in the mouth. Such a formulation is called “oral dispersibility”. The formulation typically comprises a carrier that will be pharmaceutically acceptable for this purpose (and veterinary acceptable when administered to non-human animals).

  The daily dose of desmopressin measured as the free base will generally be from 0.5 or 1 μg to 1 mg per dosage form. In one preferred dosage range, the dosage will typically be in the range of 2 μg to 800 μg, preferably 10 μg to 600 μg per dosage form. Relatively small doses (eg, lower doses compared to those described above or provided in the art), eg, 0.5 ng to 20,000 ng, preferably 0.05 mcg (50 ng) to 10 mcg (10,000 ng), more preferably 0.1 mcg (100 ng) to 2000 ng is also specifically considered. If one dosage form is administered per day, as is usual with PNE and nocturia, this is typically the dosage per dosage form. When the daily dose is administered in two or more doses, typically as in central diabetes insipidus, the amount of active compound per dosage form is reduced accordingly. Effective daily doses will depend on the individual patient's condition and should therefore be determined within the ordinary skill in the art for any particular patient. Other active ingredients can be present whether or not they are peptides.

  The pharmaceutical dosage form of the present invention is configured to supply active ingredients to the oral cavity. The effective can be absorbed through the sublingual mucosa for systemic distribution.

  Various formulations suitable for delivering other active ingredients for absorption from the oral cavity are known. Such formulations may be useful in the present invention. One of them is a solid formulation that disintegrates in the buccal side, or an active ingredient, a saccharide containing lactose and / or mannitol, 0.12-1.2 w / w% agar based on the solid ingredient, 400 mg / A preparation that has a density of ml to 1,000 mg / ml, is strong enough to handle, and in fact produces enough strength to withstand removal from a blister pack without collapse. Such formulations, and methods for their production, are disclosed in US-A-5466464, see the patent for further details.

  In this embodiment of the invention, the saccharide will vary depending on the quality and amount of the active ingredient used, but in the formulation at least 50 w / w%, preferably 80 w / w% or more, based on total solid ingredients More preferably, it can be used in an amount of 90 w / w% or more.

  There are no special restrictions on the type of agar, but those listed in the Japanese Pharmacopoeia are preferred. Examples of agar listed include agar powders PS-7 and PS-8 (manufactured by Ina Shokuhin).

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

  To produce a formulation according to this embodiment of the invention, lactose and / or saccharides containing mannitol are suspended in an agar aqueous solution, filled into a mold, coagulated into a jelly-like form, and then dried. The concentration of the agar aqueous solution may be 0.3 to 2.0%, preferably 0.3 to 0.8%. The agar aqueous solution is in such an amount that the mixing ratio of the agar based on the solid component is 0.12 to 1.2 w / w%, but preferably the agar solution is 40-60 w / w based on the solid component. What is necessary is just to use in the quantity which becomes w%.

  Other known formulations for delivering active ingredients intended for absorption from the oral cavity are the dosage forms disclosed in US-A-6024981 and US-A-6221392. These dosage forms are hard, compressed, fast-dissolvable dosage forms configured for direct oral administration, comprising a matrix containing the active ingredient and a non-direct compression filter and lubricant, said dosage form being a patient Of about 2 Newtons (N) having a friability of about 2% or less when tested in the United States Pharmacopeia. , Preferably having a hardness of 15 to 50 N in some cases. US-A-6024981 and US-A-6221392 disclose further details and features of these dosage forms and methods of making them.

  Preferably, the dosage form according to this embodiment of the invention dissolves in the patient's mouth in about 90 seconds or less (preferably 60 seconds or less, most preferably 45 seconds or less). Desirably, the dosage form includes at least one particle. The particles are an active ingredient and a protective material. These particles can include immediate release particles and / or sustained release particles.

  A particularly preferred formulation according to this embodiment of the present invention provides a hard, compressed, fast dissolving tablet configured for direct oral administration. The tablets contain particles made from the active ingredient and a protective material. These particles are provided in an amount of about 0.01 to about 75% by weight, based on the weight of the tablet. Tablets further include a matrix made from a non-direct compression excipient, a wicking agent, and a hydrophobic lubricant. The tablet matrix includes at least about 60% rapidly water soluble components based on the total weight of the matrix material. The tablets have a hardness of about 15 to about 50 Newtons as measured in the United States Pharmacopeia and a friability of less than 2% and dissolve spontaneously in the patient's mouth in less than 60 seconds, thereby liberating the particles. And configured to be stored in bulk.

  Finely granulated or powdered saccharides known as non-direct compression sugars can be used as matrix excipients in this embodiment of the invention. This material is easily dissolved in a matter of seconds when wetted by saliva in the mouth, partly because of its chemical composition and partly because of its fine particle size. This not only means that the material can contribute to the dissolution rate of the dosage form, but the excipients are “sandy” while the patient holds the dissolving dosage form in the mouth. It also means that it does not contribute to the “feeling” or “gritty” texture of the tongue and thus adversely affecting the feeling of sensory irritation when taking the dosage form. In contrast, direct compressions of the same saccharide are usually granulated and processed to make the saccharide larger and more suitable for compaction. These saccharides are water-soluble, but cannot always be solubilized with sufficient speed. As a result, these sugars can contribute to a rough or sandy texture when dissolved. The dissolution time in the mouth can be measured by observing the dissolution time of the tablet in water at about 37 ° C. The tablets are immersed in water without forced stirring or with minimal stirring. The dissolution time is the time determined by visual observation from the time of immersion until the rapidly water-soluble component in the tablet is substantially completely dissolved.

  Particularly preferred excipients according to the present invention are non-direct compression sugars and sugar alcohols meeting the specifications discussed above. Such sugars or sugar alcohols include but are not limited to dextrose, mannitol, sorbitol, lactose and sucrose. Of course, dextrose can exist, for example, either as a direct compression sugar, ie, a sugar that has been altered to increase its compression rate, or an uncompressed sugar.

  In general, the advantage of the formulation may be the matrix. Thus, the excipient ratio can approach 100%. In general, however, non-direct compression excipients useful according to the present invention range from about 25 to about 95%, preferably from about 50 to about 95%, more preferably from about 60 to about 95%.

  The amount of lubricant used may generally range from about 1 to about 2.5% by weight, more preferably from about 1.5 to about 2% by weight. Useful hydrophobic lubricants according to the invention include alkali stearates, mineral stearates and vegetable oils, glyceryl behenate and sodium stearyl fumarate. A hydrophilic lubricant can also be used.

  Useful protective materials according to this embodiment of the present invention can include any polymer commonly utilized to form microparticles, matrix-type microparticles, and microcapsules. One of these is cellulosic materials such as naturally occurring cellulose and synthetic cellulose derivatives, acrylic polymers and vinyl polymers. Other simple polymers include proteinaceous materials such as gelatin, polypeptides and natural and synthetic shellacs and waxes. Protective polymers may also include ethyl cellulose, methyl cellulose, carboxymethyl cellulose, and acrylic resin materials sold under the EUDRAGIT registered trademark by Rhone Pharma GmbH of Vitelstadt, Germany.

  The matrix may include a wicking agent, a non-foaming disintegrant and a foaming disintegrant in addition to the raw materials previously discussed. A wicking agent is a composition that has the ability to draw water into a dosage form. They serve to transport moisture into the dosage form. In this manner, the dosage form can be dissolved from the inside as well as from the outside.

  Any chemical that can function to transport moisture as discussed above may be considered a wicking agent. Wicking agents include some conventional non-foaming disintegrants. These include, for example, microcrystalline cellulose (Avicel PH200, Avicel PH101), Ac-Di-Sol (crosscamellose sodium) and PVP-XL (crosslinked polyvinylpyrrolidone), starches and modified starches, polymers, and Arabic and xanthan Of rubber is included. Hydroxyalkyl celluloses such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, and compounds such as carbopol can also be used.

  The normal range of non-foaming disintegrants used in normal tablets may be about 20%. However, the amount of disintegrant used was generally in the range of 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 about 2 to about 12%, preferably from 2 to about 5%.

  Of course, if desired, a non-foaming disintegrant that cannot act to wick moisture can be included. In either case, it is preferred to use a rapidly water soluble non-foaming disintegrant or wicking agent and / or to minimize the use of a generally water insoluble wicking or non-foaming disintegrant. Ingredients that cannot be dissolved rapidly, but not rapidly dissolved in water, when used in sufficient quantities, can adversely affect the sensory stimulating properties of the tablet as it dissolves in the mouth and are therefore minimized Should. Of course, wicking agents or non-foaming disintegrants that are rapidly water soluble as discussed herein can be used in larger quantities and they do not increase the roughness of the formulation upon dissolution. Preferred wicking agents according to the present invention include cross-linked PVP, but their amount should be adjusted so that they are not rapidly water soluble.

  Furthermore, it is desirable to use foam pairs in combination with other listed ingredients to improve the material's disintegration profile, sensory stimulation properties, and the like. Preferably, the effervescent pair is provided in an amount of about 0.5 to about 50 wt%, more preferably about 3 to about 15 wt%, based on the weight of the final tablet. It is particularly preferred to provide a sufficiently foamable material so that the gas released when exposed to the water environment is less than about 30 cm.

  The term “foaming pair” includes compounds that release a gas. A preferred foam pair releases gas by a chemical reaction that occurs when the foamable collapse pair is exposed to oral water and / or saliva. This reaction is mostly the result of a reaction between a soluble acid source and an alkali hydrogen carbonate or carbonate source. The general reaction of these two compounds produces carbon dioxide gas upon contact with water or saliva. Such materials, which are activated with water, will disintegrate the tablet when exposed to water, but not at that time, so they will generally remain in an anhydrous or stable hydrated form that absorbs little or no moisture. There must be. The acid source may be any that is safe for human consumption and generally includes edible acids such as citric acid, tartaric acid, malic acid, furnaric acid, adipic acid, and succinic acid. And acid and hydride antacids. Examples of the carbonate source include carbonates and bicarbonates that are sold by drying such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate, and the like. Also included are reactants that release oxygen or other gases that are safe for human consumption.

  In the case of tablets that can be dissolved in the mouth according to the present invention, both the amount and type of disintegrant is effervescent or non-foaming, and combinations thereof, the tablets provide a pleasant sensory irritation in the patient's mouth. It is preferred that the amount provided is sufficient to provide. In some cases, when the tablet disintegrates in the mouth, the patient must be able to perceive a foaming sound or a distinct sense of foaming. In general, the total amount of wicking agent, non-foaming disintegrant and foaming disintegrant should be in the range of 0-50%. However, it should be emphasized that the formulations of the present invention dissolve rapidly and therefore the need for disintegrants is minimal. As shown in the Examples, appropriate hardness, degree of wear and dissolution time can be obtained without a foaming disintegrant or a high content of wicking agent.

  Using non-direct compression excipients eliminates the need for many conventional processing steps such as granulation and / or the need to purchase more expensive pre-granulated compressible excipients. At the same time, the resulting dosage form is a balance between performance and stability. It is strong enough to normally manufacture using direct compression. It is strong enough to be stored or packaged in roses. Furthermore, it dissolves rapidly in the mouth while minimizing the unpleasant sensation of conventional disintegrating tablets to the extent possible.

Formulations according to embodiments of the present invention include:
(A) forming a mixture comprising a matrix comprising the active ingredient and a non-direct compression excipient and lubricant;
(B) compressing the mixture to form a number of hard compressed rapidly disintegrating dosage forms comprising an active ingredient distributed in a mouth-dissolvable matrix, and optionally,
(C) storing the dosage form in roses before packaging;
It can manufacture by the method containing. In a preferred embodiment, the dosage form is then packaged in the interior space of the package such that there is at least one per package. In a particularly preferred embodiment, the dosage form is then packaged inside the package such that there is more than at least one per package. Direct compression is the preferred method of forming the dosage form.

  Another known formulation for delivering active ingredients for absorption from the oral cavity is the dosage form disclosed in US-A-6200604, which penetrates the drug through the buccal, sublingual and gingival mucosa. Includes agents capable of oral administration in combination with effervescent agents used as penetration enhancers that affect sex. In the context of the present invention, the drug is desmopressin and in most embodiments is administered through the sublingual mucosa. In the formulations of this embodiment of the invention, the foaming agent can be used alone or in combination with other penetration enhancers that lead to an increase in the rate and extent of oral absorption of the active drug.

The formulation or dosage form according to this embodiment of the invention must include an amount of foaming agent sufficient to assist the penetration of the drug through the oral mucosa. Preferably, the foaming agent is provided in an amount of about 5% to about 95% by weight, more preferably about 30% to about 80% by weight, based on the weight of the final tablet. Gas released by exposing the tablet to an aqueous environment, to be less than about 30 cm ³ greater than about 5 cm ^3, particularly preferably provide enough foam material.

  The term “foaming agent” includes compounds that release a gas. Preferred foaming agents release gas by a chemical reaction that occurs when the foaming agent (foaming pair) is exposed to mouth water and / or saliva. This reaction is most often the result of a reaction between a soluble acid source and a carbon dioxide source such as an alkali carbonate or alkali bicarbonate. The general reaction of these two compounds produces carbon dioxide gas upon contact with water or saliva. Such materials, which are activated with water, will disintegrate the tablet when exposed to water, but not at that time, so they will generally remain in an anhydrous or stable hydrated form that absorbs little or no moisture. There must be. The acid source may be any that is safe for human consumption and is generally an edible acid such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acid and hydrogen. A chemical antacid is included. The carbonate sources preferably include carbonates and bicarbonates that are sold dry such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate and the like. Also included are reactants that release oxygen or other gases that are safe for human consumption.

  The blowing agent (s) useful in this embodiment of the invention is not necessarily based on the reaction that forms carbon dioxide. Reactants that release oxygen or other gases that are safe for human consumption are also considered within the scope of the present invention. When the foaming agent contains two components that react with each other, such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, it is preferred that the proportions of the components are equivalent providing equal equivalents. For example, if the acid used is diprotic, twice the amount of monoreactive carbonate base or equal amount of direactive base should be used to achieve complete neutralization. However, in other embodiments of the invention, the amount of either the acid source or the carbonate source can exceed the amount of the other component. This may help to enhance the flavor and / or performance of tablets containing either component in excess. In such a case, an excess amount of either component is allowed to remain unreacted.

  Such dosage forms may further comprise an amount of pH adjusting material added to the amount required for foaming. For drugs that are weakly acidic or basic, the pH of the aqueous environment affects the relative concentrations of the ionized and unionized forms of the drug present in solution, according to the Henderson-Hasselbach equation there is a possibility. The pH solution in which the foaming pair is dissolved is slightly acidic due to the release of carbon dioxide. The pH of the local environment, e.g., the pH of the saliva in direct contact with the tablet and the drug dissolved from the tablet, allows a pH-adjusting substance in the tablet to control the relative ratio of the ionized and non-ionized forms of the drug. Can be adjusted by incorporating. In this manner, the dosage form can be optimized for each specific drug. If the non-ionized drug is known or suspected to be absorbed across the cell membrane (transcellular absorption), the pH of the local environment (within the tolerance limits for the subject) It is preferable to change to a level that is convenient for the drug. Conversely, if the ionized form dissolves more easily, the local environment should be convenient for ionization.

  Preferably, the foaming material and the pH adjusting material should not compromise the water solubility of the drug so that the dosage form allows a sufficient concentration of drug to be present in the non-ionized form. Therefore, the ratio of pH adjusting substance and / or foaming substance should be adjusted according to the drug.

  Suitable pH adjusters for use in the present invention include any weak acid or weak base in an amount in addition to that required for foaming, or preferably a buffer system that is not harmful to the oral mucosa. Suitable pH adjusters for use in the present invention include, but are not limited to, any acid or base previously mentioned as the effervescent compound, disodium hydrogen phosphate, sodium dihydrogen phosphate and corresponding potassium. Salt.

  The dosage form of this embodiment of the invention includes one or more other ingredients to enhance absorption of the pharmaceutical ingredient through the oral mucosa and to improve the disintegration profile and sensory stimulation properties of the dosage form. Preferably included. For example, the contact area between the dosage form and the oral mucosa and the oral residence time of the dosage form can be improved by including a bioadhesive polymer in the drug delivery system. See, for example, “Mechanical Studies on Inferred Permeability Enhancement” (1997) by Jonathan Eichman, which is incorporated herein by reference. Foaming also increases the residence time of the bioadhesive due to its mucus release properties, thereby increasing the residence time for drug absorption. Examples of bioadhesives used in the present invention include, but are not limited to, Carbopol 934P, Na-CMC, Methocel, Polycarbophil (Noveon AA-1) HPMC, Na alginate, Na hyaluronate, and others Natural or synthetic bioadhesives.

  The dosage form according to this embodiment of the invention can also include a suitable non-foaming disintegrant in addition to the foam-forming agent. Examples of non-foaming disintegrants include, but are not limited to, microcrystalline cellulose, croscarmellose sodium, crospovidone, starch, corn starch, potato starch and their modified starches, sweeteners, clays such as bentonite, alginic acid Rubbers such as salt, agar, guar, locust bean, karaya, pectin, and tragacanth are included. The disintegrant can constitute up to about 20% by weight of the total weight of the composition, preferably about 2 to about 10%.

  In addition to the particles according to this embodiment of the invention, the dosage form may also include glidants, lubricants, binders, sweeteners, flavoring and coloring ingredients. Any conventional sweetener or flavoring ingredient can be used. Sweeteners, flavoring ingredients, or combinations of sweeteners and flavoring ingredients can be used as well.

  Examples of binders that can be used include gum arabic, tragacanth, gelatin, starch, cellulose materials such as methylcellulose and sodium carboxymethylcellulose, alginic acid and its salts, magnesium silicate, aluminum silicate, polyethylene glycol, guar gum, polysaccharide acid, bentonite , Sugars, invert sugars and the like. The binder can be used in an amount of up to 60% by weight of the total composition, preferably about 10-40%.

  Examples of the colorant include titanium dioxide, F.I. D. & C. Examples include dyes suitable for food such as dyes known as dyes, and natural colorants such as grape peel extract, beet red powder, β-carotene, anato, carmine, turmeric, and paprika. The amount of colorant used may range from about 0.1% to about 3.5% by weight of the total composition.

  The perfume incorporated into the composition can be selected from synthetic and flavoring and / or natural oils, extracts from plants, leaves, flowers, fruits and the like, and combinations thereof. These perfumes include cinnamon oil, winter green oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar oil, nutmeg oil, sage oil, bitter almond oil, and senna oil. it can. Citrus oils including vanilla, lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and the like are also useful as perfumes. Perfumes that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum perfumes, and mixtures thereof. The amount of flavoring agent may depend on several factors, including the desired sensory stimulating effect. The perfume can be present in an amount ranging from about 0.05% to about 3% by weight, based on the weight of the composition. Particularly preferred flavors are grape and cherry flavors and citrus flavors such as orange.

  One aspect of the present invention provides a solid oral tablet dosage form suitable for sublingual administration. Prosthetic excipients can be used to facilitate tableting. It is desirable that the excipient further assists in rapid dissolution of the dosage form in the mouth. Examples of suitable excipients include but are not limited to mannitol, dextrose, lactose, sucrose, and calcium carbonate.

  Tablets can be manufactured by direct compression, wet granulation, or any other tablet manufacturing technique, as described in US-A-6200604. The dosage form can be administered to a human or other mammalian subject by placing it in the subject's mouth and holding it under the tongue (for sublingual administration). The dosage form begins to spontaneously collapse due to moisture in the mouth. Collapse, especially foaming, stimulates further fluency, which further enhances collapse.

  Although the above-mentioned formulations are also encompassed within the scope of the present invention, the most preferred oral dispersible solid pharmaceutical dosage form according to the present invention comprises an open matrix network that retains a pharmaceutically effective peptide and desmopressin, said open matrix network Tissue is composed of a water-soluble or water-dispersible carrier that is inert to desmopressin.

  Pharmaceutical dosage forms comprising an open matrix network are well known from GB-A-1548022, see the patent for further details. The pharmaceutical dosage forms of the present invention can be rapidly disintegrated by water. “Rapidly disintegrates” means that the molding disintegrates in water within 10 seconds. Preferably, the molding disintegrates (dissolves or disperses) within 5 seconds. Disintegration time is measured in a manner similar to the British Pharmacopoeia (BP) 1973, Disintegration Test for Tables. This method is described in GB-A-1548022 and is outlined below.

Device No. at the bottom end to form a basket. 1. A glass or suitable plastic cylinder with a length of 80-100 mm, an inner diameter of about 28 mm, and an outer diameter of 30-31 mm, fitted with a rust-proof wire mesh disk according to the 1.70 sieve requirements.
A flat-bottomed glass cylinder with an inner diameter of about 45 mm containing water with a depth of 15 cm or more at a temperature of 36 ° C to 38 ° C.
Suspend the basket in the center of the cylinder so that the basket repeatedly rises and falls in a fixed manner, with the net just protruding slightly from the water surface at the highest position and the top edge of the basket remaining on the water surface at the lowest position.

Method A single molding is placed in the basket and the basket is raised and lowered in such a way that the complete lifting and lowering motion is repeated at a rate equal to 30 times per minute. The case where particles that do not easily pass through the net do not remain on the net is the collapse of the molded product. Such particles should not remain after 10 seconds.

  The term “open matrix network” means a network of water-soluble or water-dispersible carrier material with interstitial interstices. The open matrix network of carrier material is generally less dense. For example, the density may be in the range of 10-200 mg / cc, for example 10-100 mg / cc, preferably 30-60 mg / cc. The density of the molding may be affected by the amount of active ingredient or any other ingredients incorporated into the article and may be outside the preferred limits of the matrix network density referred to above. An open matrix network that resembles a solid foam in structure allows liquid to enter the product through the gap and penetrate into the interior. Penetration by the aqueous medium exposes both the internal and external carrier material of the product to the action of the aqueous medium, thereby rapidly collapsing the network of carrier material. The open matrix structure is porous and enhances product disintegration compared to conventional solid molded pharmaceutical dosage forms such as tablets, pills, capsules, suppositories and vaginal suppositories. Rapid disintegration causes a rapid release of active ingredients retained in the matrix.

  The carrier material used in the products of the present invention can be any water-soluble, pharmacologically acceptable or inert to chemicals and capable of forming an open matrix network capable of rapid disintegration. Or a material dispersible in water. It is preferred to use a water-soluble material as the carrier because water-soluble materials cause the most rapid matrix disintegration when the product is placed in an aqueous medium. Particularly advantageous carriers can be formed from polypeptides such as gelatin, in particular gelatin which is especially hydrolyzed, for example by heating in water. For example, gelatin can be partially hydrolyzed by heating an aqueous solution of gelatin, for example, in an autoclave at about 120 ° C. for up to 2 hours, such as 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 w / v%, for example about 3 w / v%.

  Mammal-derived gelatin can also be used, but it has an unpleasant taste and thus masks the taste of gelatin in addition to any sweeteners and fragrances that are sometimes needed to mask the taste of the active ingredient Forced to use sweeteners and fragrances. In addition, the heating step required with the use of mammalian gelatin increases processing time and heating costs, thereby increasing the total cost of the process. Therefore, it is preferred to use fish gelatin, especially non-gelled fish gelatin, especially for desmopressin. See WO-A-0061117 for further details.

  Instead of partially hydrolyzed gelatin or fish gelatin, other carriers such as hydrolyzed dextran, polysaccharides such as dextrin and alginates (eg sodium alginate) or the carriers mentioned above with each other or with polyvinyl alcohol Mixtures with other carrier materials such as polyvinylpyrrolidone or gum arabic can be used. Instead of gelatin, modified starches as described in WO-A-0044351 can also be used, see the patent for further details. Additional carriers include water, lactose, starch, magnesium stearate, talc, vegetable oil, gum, alcohol, petroleum jelly (petroleum jelly) and the like.

  The pharmaceutical dosage form of the present invention may be in the form of a molded product. In addition to the active ingredient (s), they can incorporate various ingredients. For example, pharmaceutically acceptable adjuvants can be incorporated into the pharmaceutical dosage forms of the invention. Examples of such auxiliary agents include coloring agents, flavoring agents, preservatives (for example, bacteriostatic agents) and the like. US-A-5188825 teaches that a water-soluble active agent should be bound to an ion exchange resin to form a substantially water-insoluble active agent / resin complex. Can also be carried out here (see US-A-5188825 for further details), but in the course of the present invention, a water-soluble peptide such as desmopressin does not need to be bound to an ion exchange resin, It has been found that it can be formulated into a solid dosage form of the present invention. Accordingly, such dosage forms do not include ion exchange resins. Desmopressin is not hydrophobic, but in the case of hydrophobic peptides, surfactants may be present as taught in US-A-5827541 (see the patent for further details). . In the case of peptides with an unpleasant taste (no desmopressin), lipids such as lecithin may be present to improve patient acceptance, as taught in US-A-6156339. (See that patent for details). Other strategies for masking taste include the conversion of soluble salts to less soluble salts or to the free base, as taught in US-A-5738875 and US-A-5837287, And the method disclosed in US Pat. No. 5,976,577, that is, prior to lyophilization, a suspension of uncoated or coated coarse particles of the pharmaceutically active substance (s) in a carrier material is cooled, A method of reducing viscosity and minimizing the release of active substances during processing, and further minimizing the unpleasant taste from the peptides beyond the disintegration point of the dosage form in the mouth (for further details the patent Use).

  In the case of insoluble or poorly soluble peptides having a large particle size, xanthan gum can act as a gelatin flocculant, especially when the carrier is formed from gelatin, as disclosed in US-A-5631023. May be present (see the patent for further details).

  If the matrix is selected from the group consisting of gelatin, pectin, soy fiber protein, and mixtures thereof, one species having about 2 to 12 carbon atoms, as taught by WO-A-93223017 Or a plurality of amino acids may be present. In this formulation, the preferred amino acid is glycine, while the preferred matrix forming agent is gelatin and / or pectin, and in particularly preferred embodiments the dosage form further comprises mannitol. All adjuvants are selected to be pharmaceutically acceptable.

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

  Sublimation is preferably performed by lyophilizing a composition comprising the active ingredient and a solvent solution of the carrier material. The composition can include additional components as previously mentioned. The solvent is preferably water, but may contain a co-solvent (alcohol, such as tert-butyl alcohol) in order to improve the solubility of the chemical substance. The composition can also include a surfactant, such as Tween 80 (polyoxyethylene glycol (20) sorbitan monooleate). Surfactants can help prevent lyophilized products from sticking to the mold surface. Surfactants can also help disperse the active ingredients.

  The composition adjusts the pH of the solution from which the dosage form is prepared to 3-6, preferably 3.5-5.5, most preferably 4-5, such as 4.5 or 4.8. PH adjusters can be included. Citric acid is the preferred pH adjuster, but other adjusters including hydrochloric acid and malic acid can also be used. Such non-volatile pH adjusting agents are not removed by lyophilization or other sublimation treatments and may be present in the final product.

  The mold includes a series of cylindrical or other shaped recesses therein, each size corresponding to the desired molding size. Alternatively, the size of the mold recess may be larger than the size of the desired article, and the product can be cut to the desired size (eg, a thin wafer) after the contents are lyophilized.

  However, as described in GB-A-2111423, the mold is preferably a recess in a piece of film-like material. The film-like material can include more than one recess. The film-like material may be similar to that employed in conventional blister packaging used to package oral contraceptive tablets and similar pharmaceutical forms. For example, the film-like material can be made of a thermoplastic material having a recess formed by thermoforming. A preferred film-like material is a polyvinyl chloride film. A laminate of film-like materials can also be used.

  In one embodiment, the mold includes a metal plate (eg, an aluminum plate) that includes one or more recesses. In a preferred method using such a mold, the mold is cooled with a cooling medium (eg, liquid nitrogen or solid carbon dioxide). Once the mold is cooled, a predetermined amount of water containing the carrier material, active ingredient and any other desired ingredients is fed into the recess (s). Once the contents of the recess (s) have frozen, the mold is subjected to reduced pressure and, if desired, controlled heat to aid sublimation. The pressure may be less than about 4 mmHg. GB-A-1548022 teaches that it is preferable to employ pressures of less than 0.3 mmHg, for example 0.1-0.2 mmHg. The lyophilized product can be removed from the mold recess and stored in a hermetic jar or other suitable storage container for future use, for example. Alternatively, the lyophilized product can be encapsulated with a film-like material as described in GB-A-2111423.

  A recently developed method useful for making a pharmaceutical dosage form according to the present invention is described in GB-A-2111423 (see the patent for further details). This method involves freezing the composition in the mold by filling the mold with a composition containing a predetermined amount of the active ingredient and a partially hydrolyzed gelatin solution, and passing a gaseous cooling medium over the mold. And then subliming the solvent from the frozen composition to produce a network of partially hydrolyzed gelatin that retains the active ingredient.

  To help ensure a uniform thickness of the product, the side wall or walls of the mold are diverged outward from the base and perpendicular to the surface of the composition as described in GB-A-2119246. And at least 5 ° (see the patent for further details).

  Alternatively or additionally, the pharmaceutical dosage form of the present invention comprises freezing a composition comprising a first solvent solution of a water-soluble or water-dispersible carrier material inert to the active ingredient, frozen composition Producing a product having a network of carrier components by sublimating the first solvent from the product, and adding a solution or suspension of a non-aqueous second solvent containing a predetermined amount of the active ingredient to the product , And allowing or causing the evaporation of the second solvent, can be prepared by methods as described in GB-A-2114440.

  Alternatively or additionally, the pharmaceutical dosage form of the present invention comprises introducing a droplet-like liquid medium directly under the surface of the cooling liquid maintained at a temperature below the freezing point of the liquid medium, GB-A- 2111184, wherein the coolant is immiscible and inert to the liquid medium, and the liquid droplets float toward the surface in the coolant and freeze. So as to form spherical particles, having a greater density than both the liquid medium and the resulting frozen particles. The frozen spherical particles can be collected on or near the top surface of the coolant. See GB-A-2111184 for further details.

  The dosage form according to the present invention has improved bioavailability. These dosage forms are intended to be taken orally and are very suitable for that purpose. They disperse rapidly in the mouth and can be placed, for example, under the tongue (under the tongue).

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

  The present invention provides a method of postponing urination, a method of treating or preventing incontinence, primary nocturnal enuresis (PNE), nocturia and / or central diabetes insipidus. Thus, an effective and generally non-toxic amount of desmopressin is administered through the sublingual mucosa, for example, in the dosage form described above. Any other disease or condition that can be treated or prevented with desmopressin can be similarly addressed by the means of the present invention. The invention therefore extends to the use of desmopressin in the manufacture of pharmaceutical preparations that can be absorbed sublingually. The invention also extends to a pack comprising a pharmaceutical dosage form capable of sublingual desmopressin absorption along with instructions for placing the dosage form under the patient's tongue.

  A method of preparing desmopressin packaging dosage forms is also encompassed by the present invention, which combines a pharmaceutical dosage form capable of sublingual desmopressin absorption and instructions for placing the dosage form under the patient's tongue. Including that. The instructions for use may be printed, for example, on a package containing the dosage form when sold or dispensed, or may be on a product information leaflet or on an insert in the package.

  In addition to desmopressin, other peptides can be formulated into the formulations described above. Accordingly, the present invention extends to pharmaceutical dosage forms of pharmaceutically effective peptides configured for oral absorption.

  According to a further aspect of the invention, there is provided a solid pharmaceutical dosage form, for example for oral administration, said pharmaceutical dosage form comprising a pharmaceutically effective peptide and an open matrix network holding the peptide, The matrix network is composed of a water-soluble or water-dispersible carrier material that is inert to the peptide.

  WO-A-9921579 discloses oral vaccines consisting of rapidly dissolving dosage forms, but there is no disclosure of pharmaceutically effective peptides that retain their activity after administration. The experimental study of WO-A-921579 shows only the presence in the saliva of IgA antibodies against tetanus toxoid following administration of tetanus toxoid by means of an assisted rapid dissolving dose vaccine formulation. The formulations of the present invention are not vaccines and do not contain adjuvants.

  The pharmaceutical dosage form of this aspect of the invention comprises a pharmaceutically effective peptide. Such peptides may themselves be effective directly, or they may have one or more effective metabolites, i.e. they are prosthetic to a fundamentally or truly effective essential ingredient. You can drag. The peptide can have, for example, 2 to 20, preferably 5 to 15 amino acid residues (the L-isomer is generally predominant, at least a portion of which is the D-isomer) ). Peptides can be linear, branched, or cyclic and can contain natural residues or substituents, or residues or substituents that are not commonly or found in natural peptides or proteins. Where appropriate, pharmaceutically acceptable salts, simple adducts and tautomers are also included.

Examples of peptides practically formulated by the present invention, somatostatin and cyclo _{(MeAla-Tyr- D -Trp-Lys} -Val-Phe) and cyclo _{(Asn-Phe-Phe- D -Trp-} D -Lys- Somatostatin analogs including Thr-Phe-GABA), enkephalins including Met ⁵ -enkephalin and Leu ⁵ -enkephalin, atociban (1-deamino-2- _D -Tyr- (OEt) -4-Thr-8-Om- oxytocin) oxytocin analogs such as, triptorelin _(6- D -Trp-GnRH), leuprolide ^{_{([D -Leu 6, Pro 8}} -NHEt] -GnRH), degarelix _{(Ac- D} -2NaI- _D -4Cpa- _D - 3Pal-Ser-4Aph (L-hydroolo _{Le) - D -4Aph (Cbm) -Leu} -Ilys-Pro- D -Ala-NH 2, wherein, 2NaI is 2-naphthylalanine, 4Cpa is 4-chloro phenylalanine, 3Pal is 3-pyridyl-alanine ILys is N (8) -isopropyllysine, 4Aph is 4-aminophenylalanine and Cbm is a carbamoyl group), and the like in US-A-5925730 and US-A-4072668 Other disclosed GnRH antagonists, and vasopressin analogs such as desmopressin. Since agonists are effective at lower doses than antagonists, it is particularly preferred to formulate natural active peptide agonists such as those described above according to the present invention.

  The dosage will be determined by the 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 present invention extends to the use of peptides in the manufacture of dosage forms as described above for the treatment or prevention of diseases or conditions treatable or preventable by peptides.

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

Low-dose analysis and application As indicated above, the recommended dose and desmopressin dose and plasma / plasma / serum concentrations that are 5-40% of the plasma / plasma / serum levels obtained are It is therapeutically effective and in some cases safer for certain disease states such as CDI, PNE, and additional clinical signs requiring pharmacological concentrations of urine.

  Clinical observations of adult boys and girls who are treated with desmopressin for a condition known as nocturia (which causes frequent nocturia) suggest that a lower dose of desmopressin is desirable. In this patient population, standard nasal and oral administration of desmopressin unexpectedly has a high incidence of hyponatremia, a condition in which plasma / plasma / serum sodium drops to abnormally low levels. Caused. Hyponatremia can result in seizures, arrhythmias, cerebral edema and death. Oral doses of desmopressin ranged from 100 to 400 mcg and intranasal doses ranged from 10 to 20 mcg. Although these doses reduce the incidence of nocturia, hyponatremia is associated with a decrease in dose due to hyperhydration and dilution of plasma / plasma / serum sodium. It was suggested that it is unnecessarily high, causing an excessive duration of pharmacodynamic effects on urine concentration. Lower doses of desmopressin result in adequate but not excessive antidiuresis 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, more preferably about 0.00. The range is from 5 pg / mL to about 5.0 pg / mL. These amounts and ranges of desmopressin are not limited, as outlined below, but are intravenous (bolus, injection), subcutaneous (bolus, injection, depot), intranasal, transmucosal (Buccals and sublinguals such as orally dispersible tablets, wafers, films, and foamed preparations, conjunctiva (eye drops), rectum (suppositories, enemas)), transdermal (passive absorption patches, gels, creams, ointments or Iontophoretic agents) or intradermally (bolus, injection, depot) can be administered by any method known in the art. Further, a pharmaceutical composition comprising desmopressin in an amount that provides the plasma / plasma / serum desmopressin concentration described above can be prepared by the use of the method and the carrier or by any other method well known in the art.

The dose range of desmopressin outlined above can provide an appropriate antidiuretic effect when administered by various routes as summarized in the examples below.

  Low doses of desmopressin treat central diabetes insipidus, prevent primary nocturnal enuresis, prevent nocturia, treat clinical disorders associated with nocturia, including but not limited to sleep disorders It may be an effective treatment for clinical signs such as prevention of incontinence (tension, impulsiveness, etc.) and postponement of urination during arousal.

  It is also possible to create a specific formulation of desmopressin with enhanced absorption and improved systemic bioavailability. These formulations produce additional pharmacological effects at each point along the dose response curve, thereby amplifying desmopressin activity even at low doses.

  The invention is illustrated in more detail by the following examples. Unless expressly stated otherwise, all parts and percentages are by weight.

Example 1 200 μg desmopressin oral dispersible dosage form A glass beaker is filled with spray dried fish gelatin (4 g) and mannitol (3 g). Purified water (93 g) is then added and brought into solution by stirring using a magnetic stir bar. 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 to each of a series of blister pockets having a preformed pocket diameter of about 16 mm. The blister stack may comprise PVC coated with PVdC. The administered dosage unit is then frozen in a freezing tunnel at a temperature of −110 ° C. with a residence time of 3.2 minutes, and the frozen dosage unit is then frozen at a temperature of −25 ° C. (± 5 ° C.). It was kept in a vertical freezer for more than 1.5 hours. The dosage unit is then lyophilized overnight at a pressure of 0.5 mbar while raising the shelf temperature from the initial 10 ° C. to + 20 ° C. Prior to removal, the dosage units were examined for moisture by dry trace and by pressurized moisture test.

Thus, an oral dispersible dosage form of desmopressin is prepared according to the general procedure shown 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 necessary) (pH adjuster) Up to pH 4.8 Purified water (removed during processing)

Example 2 400 μg Desmopressin Oral Dispersible Dosage Form The procedure of Example 1 herein is followed except that the amount of desmopressin per unit dosage form is 400 μg.

Example 3 800 μg Desmopressin Oral Dispersible Dosage Form The procedure of Example 1 herein is followed except that the amount of desmopressin per unit dosage form is 800 μg.

Example 4 200 μg Desmopressin Oral Dispersible Dosage Form Desmopressin Dosage Form, Oral Dispersible Dosage Form Using the following ingredients per unit dosage form according to the general procedure shown in Example 1 of WO-A-0061117 Was prepared.
Desmopressin (PolyPeptide Laboratories, Sweden)
200 μg
Mannitol EP / USP (Roquette, Mannitol 35)
6mg
Fish gelatin USNF / EP 10mg
Citric acid (if necessary) (pH adjuster) Up to pH 4.8 Purified water (removed during processing)

Example 5 400 μg Desmopressin Oral Dispersible Dosage Form The procedure of Example 4 herein was followed except that the amount of desmopressin per unit dosage form was 400 μg.

Example 6 800 μg Desmopressin Oral Dispersible Dosage Form The procedure of Example 4 herein was followed except that the amount of desmopressin per unit dosage form was 800 μg.

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

(Comparative example 2) 200 microgram desmopressin conventional tablet The tablet containing the following components was prepared using the usual wet granule method.
Desmopressin (PolyPeptide Laboratories, Sweden)
200 μg
Lactose (Pharmacato 150M, DMV, Netherlands) 120mg
Potato starch (Lickeby AB, Sweden) 77mg
PVP (Kollidon 25, BASF, Germany) 1.8mg
Magnesium stearate (Peter Greven, Germany) 1mg
Granulating liquid (water, ethanol) (removed during processing)

Comparative Example 3 100 μg desmopressin conventional tablet The procedure of Comparative Example 2 herein was followed except that the amount of desmopressin was 100 μg per tablet.

Example 7 Bioavailability of desmopressin administered according to Examples 4-6 Study plan In this study, 24 healthy non-smoking male volunteers were enrolled. This study was planned as a one-center, open-label, randomized, balanced, four-way cross-phase I study. For each subject, desmopressin as a 200 μg, 400 μg and 800 μg oral dispersible dosage form (Examples 4, 5 and 6 respectively) in a randomized order and as an intravenous bolus (Comparative Example 1) 2 μg was administered (Comparative Example 1). There was a 72 hour wash period between doses. Subjects were asked to avoid food, chewing gum, etc. to standardize the buccal mucosa before administering the mouth-dispersible tablets. Subjects were allowed to brush their teeth in the morning before dosing without using toothpaste.

Blood samples Blood samples to determine the plasma concentration of desmopressin were collected on the following schedule: pre-dose and 15, 30, 45 minutes after administration, 1, 1.5, 2, 3, 4, 6 8, 10, 12, and 24 hours. Additional blood samples were taken at 5 and 10 minutes after intravenous administration.

Assay Desmopressin concentration in plasma was measured by a validated RIA method.

Pharmacokinetic Analysis Desmopressin concentrations in plasma were measured using commercially available software WinNonlin ™ Pro, ver. Individual volunteers in each dose group were analyzed using a non-compartmental method using 3.2 (Pharsight Corporation, USA). Plasma concentration values below the limit of quantification (LOQ), followed by values above the limit of quantification (LOQ) were set to “LOQ / 2” for descriptive statistics on NCA analysis and concentration. Values below LOQ that do not continue to exceed LOQ were excluded from the NCA analysis and set to zero in the descriptive statistics on concentration.

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

  The pharmacokinetics of desmopressin is linear when administered as the oral dispersible dosage form of Example 4, 5 or 6.

Comparative Example 4 Bioavailability of desmopressin administered in Comparative Examples 2 and 3 This study, planned as an open-label, single-dose, 3-way crossover study, involved 36 healthy male volunteers (white race) , Black and Hispanic). Each subject received 200 μg desmopressin as one 200 μg tablet (Comparative Example 2), 200 μg desmopressin as two 100 μg tablets (Comparative Example 3), and intravenous bolus in a randomized order (Comparative Example 1) 2 μg was administered.

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

Example 8 Crossover Study Examining Antidiuretic Effects of Three Levels of Low Dose Desmopressin The following example is administered by 2 hours of intravenous infusion in overhydrated healthy, non-smoking male and female volunteers. A study showing the antidiuretic effects of three levels of low-dose desmopressin is described. In summary, this is an open-label, cross-sectional study of 8 healthy, overhydrated, non-smoking boys and girls aged 18-40. Subjects were dosed initially at a dose of 0.5 ng / kg, then at a dose of 1.0 ng / kg, and finally at a dose of 2.0 ng / kg. Pharmacodynamic and pharmacokinetic parameters were evaluated at each dose level. A 2-day (48 hour) wash period was adhered between doses.

  The study evaluated 8 subjects, 5 boys and 3 girls. Their body weights were 85.9, 65, 80.9, 63.3, 72.5, 67.6, 63.5, and 54.5 kg. The average body weight of the 8 subjects is 69.15 kg, which is very close to the standard 70 kg weight estimate based on the dose and blood concentration of desmopressin in this study. On the first day of the study (the first day of administration), subjects were overhydrated by drinking a volume of water equal to 1.5% of their body weight, and overhydration was maintained by replacing urinary excretion with water intake. . In this study, 0.5, 1.0 and 2.0 ng / kg desmopressin in 100 mL sterile saline (0.9%) (USP injection) were used. Three levels of desmopressin infusion (one of each of the above concentrations) were administered at a constant rate of I.D. V. Administered as an infusion. Each subject remained in the clinic for a total of 7 days from one day before the first dose to one day after the last dose. The initial dose was 0.5 ng / kg. Following completion of desmopressin infusion, subjects were urinated every 20 minutes and monitored until three consecutive urine collections measured urination levels above 10 mL / min. At this point, overhydration was discontinued. The urinary osmolality of urine was measured by collecting urine as a basal amount 20 minutes before the infusion and every 20 minutes from the start of the infusion 6 hours later. The specific gravity of urine was also measured. Plasma / serum sodium and plasma / serum osmolality were measured before administration and 2, 4, and 6 hours after the start of infusion. Blood samples for pharmacokinetic measurements were collected before administration, 15, 30, and 45 minutes after the start of infusion, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours. A similar procedure was repeated for 1.0 ng / kg and 2.0 ng / kg infusions. On day 6, approximately 24 hours after the third final desmopressin infusion, subjects underwent an exit screening for laboratory signs of significant signs, blood and urine.

Study criteria include urinary excretion during the period, osmolality during the period, urine specific gravity during the period, plasma / plasma / serum osmolality during the period and sodium. Statistical analysis of the above criteria was performed. The statistical analysis was descriptive and all statistical hypotheses were tested for research purposes. The following items were investigated. Evaluate each subject using three different osmolality levels (150 mOsm / kg, 200 mOsm / kg and 400 mOsm / kg) as the limit of duration of action, ie, time from “start” to “end” of action did. First, the duration of action is determined from the onset of action (ie, the first time the urinary osmolality was less than 150 mOsm / kg after dose administration) to the end of action (urinary osmolality is 150 mOsm). The time until the first time that subsequently occurs to be less than / kg, which is confirmed in the next interval unless the first time that follows is the last observation point) was defined. The second and third assessments used 200 mOsm / kg and 400 mOsm / kg as limit levels for the “start” and “end” of action, respectively. Subjects who did not have an “end of action” with respect to this definition were deleted when their urinary excretion returned to basal (> 10 mL / min) and / or when the overhydration procedure was discontinued. Total duration of action was assessed for each treatment group using the nonparametric Kaplan-Meier method. Various means for estimating the duration of action appear to give lower and upper limits on the true probability, ie the probability of desmopressin action as a function of time. Furthermore, the duration of action is indicated using the mean, SD, median, minimum and maximum values for each treatment group. Appropriate linear or non-linear models were used to examine the dose response relationship between duration of action and dose. From the individual concentration versus time curve of desmopressin, the pharmacokinetic parameters, ie AUC (area under the plasma concentration to time curve to infinity), C _max (maximum plasma concentration observed), t _max (C _max after administration) CL (total systemic clearance) V _z (distribution volume in terminal phase), AUC _t (area under plasma concentration-time curve from time 0 to time t), λ _z (logarithm of time versus concentration) First-order rate constants associated with the terminal (log-linear) portion of the plasma concentration-time curve predicted by linear regression) and t _1/2 (final half-life) were derived.

Summary of Results All three doses of desmopressin (IV infusion) were measurable in response to dose with respect to increased urine concentration (osmolality) and decreased urinary excretion. Brought diuretic effect. Also, the pharmacodynamic duration of the antidiuretic effect showed a dose response curve with the lowest dose having the shortest duration of effect. Mean maximum urine osmolality (mOsm / kg) appeared at the end of the 2 hour infusion at each dose level. Basal mean urine osmolality was 55.8, 55.8 and 55.6 for doses of 0.5, 1.0 and 2.0 ng / kg, respectively. The maximum urine osmolality was 206.0, 444.7, and 587.2 for 2 hours for doses of 0.5, 1.0, and 2.0 ng / kg, respectively. Mean minimum urinary excretion (mL / min) also appeared at the end of the 2 hour infusion for each dose level. Basal minimum urinary excretion was 18.6, 16.6 and 16.9 mL / min for doses of 0.5, 1.0 and 2.0 ng / kg, respectively. The average minimum urinary excretion was 7.1, 1.3 and 0.7 mL / min for doses of 0.5, 1.0 and 2.0 ng / kg, respectively. The duration of the antidiuretic effect was approximately 180 minutes at a dose of 0.5 ng / kg, 240-280 minutes at a dose of 1.0 ng / kg, and 360 minutes at a dose of 2.0 ng / kg. . Tables 1 to 6 and FIGS. 1 to 9 show the osmolality of urine and the excretion amount of each urine and the average value at each time.

  As shown in Tables 1-6 and FIGS. V. A low dose of desmopressin administered as an infusion over 2 hours produced a significant antidiuretic effect in response to the dose in hyperhydrated normal subjects. These doses and estimated plasma / serum concentrations of desmopressin are much more than an order of magnitude lower than today's indicated recommended and clinical practice amounts. Also, the duration of pharmacodynamic action is proportional to the dose of 1.0 and 2.0 ng / kg, providing a duration of 4-6 hours. This would be appropriate to provide the desired therapeutic effect on existing and potential new clinical signs for desmopressin. Safety and tolerance were excellent.

  The results of this study demonstrate the low-dose hypothesis for desmopressin, and are intended for patients to evaluate low-dose desmopressin for conditions such as primary nocturnal enuresis, adult nocturia, incontinence and central diabetes insipidus. Provides an empirical basis for further clinical research.

  The therapeutic efficacy of desmopressin against all these clinical signs is based on the pharmacological antidiuretic effect of desmopressin resulting in the production of smaller volumes of more concentrated urine. In patients with central diabetes insipidus, the pituitary does not produce vasopressin, a natural antidiuretic hormone, or produces very little. This deficiency causes the production of large amounts of very dilute urine that can lead to dehydration and serious metabolic abnormalities unless the patient consumes very large amounts of water. Desmopressin replaces the deficient vasopressin and restores the normal urine concentration and volume of these patients. In patients with primary nocturnal enuresis (sleeping urine), the antidiuretic effect of desmopressin reduces nocturnal urine volume, lowering the urine volume that the urinary bladder must hold, thereby reducing or eliminating the occurrence of enuresis To do.

  In patients with adult nocturia, there is nocturnal polycoma (large urine production), low bladder capacity or increased bladder sensitivity to urine output. Under all these circumstances, at night, often several times, the bladder threshold for urine retention is exceeded, producing a neural signal for urination. This causes the patient to wake up to urinate. The antidiuretic effect of desmopressin reduces nocturnal urine production, delays the time above the urination threshold, leads to a longer sleep period before urination, and reduces the number of nocturnal urinations.

  In patients with various incontinences (tension, urgency, etc.) often associated with urinary bladder abnormalities resulting from surgery, childbirth, and aging, the bladder cannot hold even a normal amount of urine. The volume threshold for urination is low and the risk of unintentional urination (incontinence) is high. Desmopressin's antidiuretic effect reduces urine production and delays crossing with the abnormally low micturition volume threshold in these patients, thus allowing postponement.

  In all the above clinical signs, or in the medical use of desmopressin, its pharmacological antidiuretic effect leading to a reduced production of more concentrated urine is the mechanism of therapeutic efficacy. This clinical study shows that desmopressin can produce this intrinsic antidiuretic effect at lower doses and lower blood concentrations than previously thought. Thus, low doses and concentrations of desmopressin can be used to treat patients with all of the above conditions.

The following are mentioned as an aspect of this invention.
[1] A pharmaceutical composition comprising 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier.
[2] The pharmaceutical composition according to [1], comprising about 0.5 ng to about 2000 ng desmopressin.
[3] The pharmaceutical composition according to [1], comprising about 0.05 μg to about 10 μg of desmopressin.
[4] The pharmaceutical composition according to [1], comprising about 0.1 μg to about 20 μg of desmopressin.
[5] The pharmaceutical composition according to [1], which is configured for intravenous, subcutaneous, transmucosal, transdermal, or intradermal delivery.
[6] The pharmaceutical composition according to [1], which is in the form of a mouth-dispersible solid.
[7] The pharmaceutical composition according to [1], further comprising an open matrix network, wherein the open matrix network includes a water-soluble or water-dispersible carrier material that is inert to desmopressin.
[8] A pharmaceutical composition comprising desmopressin and a pharmaceutically acceptable carrier, ranging from about 0.1 picogram desmopressin per ml plasma / serum to about 10.0 picogram desmopressin per ml plasma / serum A pharmaceutical composition that is effective in establishing plasma / serum desmopressin concentrations.
[9] The steady state plasma / serum desmopressin concentration ranges from about 0.5 picogram desmopressin per ml plasma / serum to about 5.0 picogram desmopressin per ml plasma / serum. Pharmaceutical composition.
[10] The pharmaceutical composition according to [8], comprising about 0.5 ng to about 2000 ng desmopressin.
[11] The pharmaceutical composition according to [8], comprising about 0.05 μg to about 10 μg of desmopressin.
[12] The pharmaceutical composition according to [8], comprising about 0.1 μg to about 20 μg of desmopressin.
[13] The pharmaceutical composition according to [8], which is configured for intravenous, subcutaneous, transmucosal, transdermal, or intradermal delivery.
[14] A product comprising a packaging material and a pharmaceutical composition included in the packaging material, wherein the pharmaceutical composition is hemophilia, von Willebrand disease, incontinence, primary nocturnal enuresis (PNE) Therapeutically effective for treating or preventing nocturia or central diabetes insipidus, and the packaging material is used to treat the pharmaceutical composition with hemophilia, von Willebrand disease, incontinence, primary nocturia Containing 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier, comprising a label indicating that it can be used to treat or prevent nocturnal syndrome (PNE), nocturia, or central diabetes insipidus Products including
[15] A method for treating or preventing a disease or condition that can be treated or prevented with desmopressin, comprising 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier for a patient Administering a daily dose of the composition.
[16] The disease or condition is selected from the group consisting of hemophilia, von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus. ] Method.
[17] Inducing an antidiuretic effect in a patient, comprising administering to the patient a daily dose of a therapeutically effective amount of a pharmaceutical composition comprising 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier. Method.
[18] The patient suffers from a disease selected from the group consisting of von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus. ] Method.

Claims (6)

  For use in the treatment or prevention of urinary incontinence, or to induce postponement of urination, comprising desmopressin and a pharmaceutically acceptable carrier in a dosage unit in which 0.5 ng to 2000 ng of desmopressin is administered by intranasal administration Pharmaceutical composition.   Establish steady plasma / serum desmopressin concentrations in urine production ranging from 0.1 picogram desmopressin per ml plasma / serum up to 10.0 picogram desmopressin per ml plasma / serum when administered to patients Comprising 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier configured for intranasal, sublingual, buccal, transmucosal, transdermal, or intradermal administration. A pharmaceutical composition for the treatment or prevention of urinary incontinence or for inducing postponement of urination.   The pharmaceutical composition according to claim 2, comprising 0.5 ng to 10 μg of desmopressin.   The pharmaceutical composition according to claim 2, comprising 0.5 ng to 2000 ng of desmopressin.   5. Establish a steady plasma / serum desmopressin concentration from 0.5 picogram desmopressin per ml plasma / serum to 5.0 picogram desmopressin per ml plasma / serum when administered to a patient. A pharmaceutical composition according to claim 1. For use in the treatment or prevention of urinary incontinence, or to induce postponement of urination, comprising desmopressin and a pharmaceutically acceptable carrier in a dosage unit dosed by intranasal administration of 0.5 ng to 600 μg of desmopressin Pharmaceutical composition.

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