JP6636893B2 - Pharmaceutical composition containing low dose desmopressin - Google Patents

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 blood pressure 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 the acetate salt and as a nasal spray, and among other indications, including central diabetes insipidus, prolonged voiding, incontinence, primary nocturnal enuresis (PNE) ) And nocturia.

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

Today, the approved label for desmopressin recommends administration in the following ranges, depending on the clinical indication and route of administration.

  The maximum plasma / plasma / serum concentration achieved with a typical intranasal dose of 20 micrograms (mcg or μg) of desmopressin for CDI or PNE is about 20% based on a 3-5% bioavailability. Will be ３０30 pg / mL. For desmopressin oral tablets with a bioavailability of only 0.1-0.15%, a standard dose of 200-400 mcg still shows peak plasma / plasma / serum levels of 20-30 pg / mL. There will be.

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

  Existing desmopressin preparations meet the needs of patients, but still need improvement. Tablets are often preferred by patients because of their ease of 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 fluid intake needs to be limited in connection with desmopressin treatment, and The message to the patient is clearer without any water intake. Further, while the above doses and plasma / plasma / serum concentrations are effective in treating CDI and PNE, standard doses of desmopressin 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 the field have appreciated 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 another aspect, the invention comprises desmopressin and a pharmaceutically acceptable carrier, wherein the desmopressin ranges from about 0.1 picograms of desmopressin per mL of plasma / plasma / serum to about 10.0 picograms of desmopressin per mL of plasma / plasma / serum. A pharmaceutical composition effective to establish a steady plasma / plasma / serum desmopressin concentration.

  In another aspect, the 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 It is therapeutically effective to treat or prevent nocturnal enuresis (PNE), nocturia, or central diabetes insipidus, wherein the packaging material has a pharmaceutical composition whose hemophilia, von Willebrand disease, A pharmaceutical composition comprising a label indicating that it can be used to treat or prevent incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus; 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, comprising administering to a patient 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable agent. Administering a therapeutically effective amount of a pharmaceutical composition comprising a carrier per day.

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

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

That is, the gist of the present invention is:
[1] a pharmaceutical composition for treating or preventing nocturia, comprising 0.5 ng to 2000 ng of desmopressin;
[2] The pharmaceutical composition of [1], further comprising a pharmaceutically acceptable carrier configured for intranasal, sublingual, buccal, transmucosal, transdermal, or intradermal administration.
[3] The pharmaceutical composition according to [1] or [2], wherein the nocturia is adult nocturia.

  According to the present invention, a pharmaceutical composition containing a low dose of desmopressin can be provided.

The present invention will be more completely understood by combining the above detailed description with the accompanying drawings.
FIG. 2 shows the urine osmolality of each subject obtained by administration of 0.5 ng / kg desmopressin. FIG. 3 shows the urinary osmolality of each subject obtained by administration of 1.0 ng / kg desmopressin. FIG. 2 shows urine osmolality of each subject obtained by administration of 2.0 ng / kg desmopressin. It is a figure which shows the urinary excretion of each subject obtained by administration of 0.5 ng / kg of desmopressin. It is a figure which shows the urinary excretion of each subject obtained by administration of 1.0 ng / kg of desmopressin. It is a figure which shows the urinary excretion amount of each subject obtained by administration of 2.0 ng / kg of desmopressin. FIG. 3 shows the mean urine osmolality obtained with 0.5, 1.0, and 2.0 ng / kg desmopressin administration. FIG. 3 is a diagram showing average urine excretion obtained by administration of 0.5, 1.0, and 2.0 ng / kg of desmopressin. FIG. 3 shows the mean urine osmolality and mean urine excretion obtained with 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 by the mouth and provides enhanced bioavailability. Available evidence indicates that desmopressin administered orally (sublingually) is not significantly absorbed (Fjellestad-Paulsen A. et al., Clin. Endocrinol. 38, 177-). 82 (1993), it is surprising that desmopressin can indeed be absorbed in this manner. It is even more unexpected that bioavailability can be improved as compared to conventional oral tablet formulations (ie, formulations swallowed by patients).

  It was also unexpectedly discovered that low doses and plasma / plasma / serum levels of desmopressin are pharmacologically active and can achieve the desired maximum therapeutic efficacy. The inventor has determined that the currently recommended doses and desmopressin doses and plasma / plasma / serum concentrations that are 5-40% of the resulting plasma / plasma / serum levels are therapeutically effective. Have been found to be safer in some cases for the treatment of additional clinical indications requiring pharmacological concentration 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 effect on urine concentration at each plasma / plasma / serum concentration point over the expected dose range Was found to be 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 a free base, or a pharmaceutically or, where appropriate, a veterinarily acceptable salt, or any other pharmaceutically or veterinarily acceptable form. Acetates are particularly preferred.

  The formulation is typically solid. It can disperse rapidly in the mouth. Such formulations are termed "orally dispersible." The formulation typically comprises a carrier that will be pharmaceutically acceptable (veterinarily acceptable when administered to a non-human animal) for this purpose.

  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 range from 2 μg to 800 μg, preferably 10 μg to 600 μg per dosage form. Relatively low 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. When one dosage form is administered per day, as is customary with PNE and nocturia, this is typically the dosage per dosage form. When the daily dose is administered in two or more doses, as is typically the case in central diabetes insipidus, the amount of active compound per dosage form is correspondingly reduced. The effective daily dose will depend on the condition of the individual patient and, therefore, should be determined for any particular patient within the ordinary skill in the art. Other active ingredients, whether or not peptides, can also be present.

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

  Various formulations are known that are suitable for delivering other active ingredients for absorption from the oral cavity. Such formulations may be useful in the present invention. One of them contains a solid formulation that disintegrates in the buccal side, or saccharides including active ingredient, lactose and / or mannitol, 0.12-1.2 w / w% agar based on solid ingredients, 400 mg / It is a preparation having a density between ml and 1,000 mg / ml, having sufficient strength to handle, and in fact, having sufficient strength to withstand removal from the blister package without collapse. Such formulations, and methods of making them, are disclosed in U.S. Pat. No. 5,466,646, see that patent for further details.

  In this embodiment of the invention, the saccharides vary in the formulation depending on the quality and quantity of the active ingredients used, but in the formulation at least 50% w / w, preferably above 80% w / w based on total solids. , More preferably 90 w / w% or more.

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

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

  To produce a formulation according to this embodiment of the invention, the saccharide, including lactose and / or mannitol, is suspended in an aqueous agar solution, filled into a mold, coagulated into a jelly-like form, and then dried. The concentration of the aqueous agar solution may be 0.3 to 2.0%, preferably 0.3 to 0.8%. The aqueous agar solution is in an amount such that the mixing ratio of the agar based on the solid components is 0.12-1.2 w / w%, but preferably the agar solution is 40-60 w / w based on the solid components. It may be used in such an amount as to be w%.

  Other known formulations for delivering active ingredients for oral absorption are the dosage forms disclosed in US-A-6024981 and US-A-6221392. These dosage forms are rigid, compressed, rapidly dissolving dosage forms configured for direct oral administration and include a matrix containing the active ingredient and a non-direct compression filter and a lubricant, wherein the dosage form comprises And has a friability of less than about 2% as tested in the United States Pharmacopeia, wherein the dosage form is at least about 15 Newtons (N). , Preferably a hardness of 15 to 50 N. 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). Also, the dosage form desirably includes at least one type of particle. The particles are the active ingredient and the protective material. These particles can include immediate release particles and / or sustained release particles.

  In a particularly preferred formulation according to this embodiment of the invention, there is provided a hard, compressed, fast dissolving tablet configured for direct oral administration. The tablet contains 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 comprise a matrix made from non-direct compression excipients, a wicking agent, and a hydrophobic lubricant. A tablet matrix includes at least about 60% of the rapidly water-soluble component, based on the total weight of the matrix material. The tablet has a hardness of about 15 to about 50 Newtons as measured by the United States Pharmacopeia, a friability of less than 2%, and dissolves spontaneously in the patient's mouth in less than 60 seconds, thereby releasing the particles. , And can be stored in bulk.

  Finely granulated or powdered sugars, known as non-direct compression sugars, can be used as excipients for the matrix in this embodiment of the invention. This material dissolves easily in a matter of seconds when wetted by saliva in the mouth, partly due to its chemical composition and partly due to its fine particle size. This not only means that the material can contribute to the dissolution rate of the dosage form, but also that the excipient may be "sandy" while the patient holds the dissolving dosage form in the mouth. It also means that it does not contribute to the "gritty" or "gritty" texture of the tongue and thus to the sensory irritation during ingestion of the dosage form. In contrast, a direct compression of the same saccharide is usually granulated and processed to make the saccharide larger and more suitable for compaction. These saccharides are water-soluble but cannot always be solubilized fast enough. 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 the water without or with minimal agitation. The dissolution time is the time determined by visual observation from the time of immersion to the time when the rapidly water-soluble component in the tablet is substantially completely dissolved.

  Particularly preferred excipients according to the 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 be present, for example, as either directly compressed sugar, ie, sugar that has been altered to increase its compressibility, or as uncompressed sugar.

  In general, the superiority of the formulation may be the matrix. Thus, the proportion of excipients can approach 100%. However, generally, non-direct compression excipients useful according to the invention will 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 present invention include alkali stearate, mineral stearates and vegetable oils, glyceryl behenate and sodium stearyl fumarate. Hydrophilic lubricants can also be used.

  Useful protective materials according to this embodiment of the 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 gelatin, polypeptides and proteinaceous materials such as natural and synthetic shellac and waxes. Protective polymers can also include ethylcellulose, methylcellulose, carboxymethylcellulose, and acrylic resin materials sold by Rhone Pharma GmbH, Baytelstadt, Germany under the registered trademark EUDRAGIT.

  The matrix may include wicking agents, non-effervescent disintegrants and effervescent disintegrants in addition to the ingredients previously discussed. Wicking agents are compositions that have the ability to draw water into a dosage form. They help transport moisture inside 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-effervescent disintegrants. These include, for example, microcrystalline cellulose (Avicel PH200, Avicel PH101), Ac-Di-Sol (croscarmellose sodium) and PVP-XL (crosslinked polyvinylpyrrolidone), starch and modified starch, polymers, and Arabic and xanthan Rubber is included. Hydroxyalkylcellulose, such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, and compounds such as carbopol can also be used.

  The normal range of the non-effervescent disintegrant used for ordinary tablets may be about 20%. However, the amount of disintegrant used generally ranged from about 2 to about 5% according to the Handbook of Pharmaceutical Excipients'.

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

  Of course, if desired, it is also possible to include non-effervescent disintegrants which cannot act to wick moisture. In both cases, it is preferred to use a rapidly water-soluble non-effervescent disintegrant or wicking agent, and / or generally to minimize the use of water-insoluble wicking or non-effervescent disintegrants. Ingredients that do not dissolve quickly and do not dissolve rapidly in water can, when used in sufficient quantities, adversely affect the tablet's organoleptic properties when the tablet dissolves in the mouth, and are therefore minimized Should. Of course, wicking agents or non-effervescent disintegrants that are rapidly water-soluble, as discussed herein, can be used in larger amounts 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.

  In addition, it is desirable to use an effervescent couple in combination with the other listed components to improve the disintegration profile, organoleptic properties, etc. of the material. Preferably, the effervescent couple is provided in an amount of about 0.5 to about 50% by weight, more preferably about 3 to about 15% by weight, based on the weight of the final tablet. It is particularly preferred to provide sufficient effervescent material such that the emitted gas upon exposure to an aqueous environment is less than about 30 cm.

  The term "foaming couple" includes compounds that release gas. Preferred effervescent couples release gas by a chemical reaction that occurs upon exposing the effervescent disintegration pair to water and / or saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source with an alkali bicarbonate or carbonate source. The general reaction of these two compounds produces carbon dioxide gas on contact with water or saliva. Such materials that are activated by water will disintegrate the tablet when exposed to water at an earlier time, and will generally be retained in an anhydrous state with little or no absorption of water, or in a stable hydrated form. There must be. The acid source can be any that is safe for human consumption, and generally includes edible acids such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acid. Acid and hydride antacids. The carbonate source preferably includes dried and sold carbonates and bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, and magnesium carbonate. Includes 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 invention, the amount and type of disintegrant, whether effervescent or non-effervescent, and combinations thereof, make the tablet produce a pleasant organoleptic sensation in the patient's mouth. Preferably, it is supplied in a controlled amount to provide it. In some cases, when the tablet disintegrates in the mouth, the patient must be able to perceive a foaming sound or a distinct sensation of foaming. In general, the total amount of wicking agent, non-effervescent disintegrant and effervescent disintegrant should be in the range of 0-50%. It should be emphasized, however, that the formulations of the present invention dissolve rapidly and therefore the need for disintegrants is minimal. As shown in the examples, appropriate hardness, wear and dissolution time can be obtained without an effervescent disintegrant or a high content of wicking agent.

  The use of 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 balances performance and stability. It is strong enough to be manufactured normally using direct compression. It is strong enough to be stored or packaged in bulk. In addition, it dissolves rapidly in the mouth, 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 the active ingredient and a matrix comprising a non-direct compression excipient and a lubricant;
(B) compressing the mixture to form a number of hard, compressed, rapidly disintegrating dosage forms containing the active ingredient distributed in an orally dissolvable matrix; and, optionally,
(C) storing the dosage form in bulk before packaging;
Can be produced by a method including: In a preferred embodiment, the dosage form is then packaged in the interior space of the packet, such that there is at least one dosage per packet. In a particularly preferred embodiment, the dosage form is then packaged inside a packet so that there is at least one more per packet. Direct compression is a preferred method of forming the dosage form.

  Other known formulations for delivering the active ingredient for absorption from the oral cavity are the dosage forms disclosed in US-A-6200604, which provide for the penetration of the drug through the buccal, sublingual, and gingival mucosa. Orally administrable agents in combination with effervescent agents used as penetration enhancers to affect sex. In the context of the present invention, the drug is desmopressin, which in most embodiments is administered across the sublingual mucosa. In the formulation of this embodiment of the invention, the effervescent 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 effervescent agent sufficient to assist penetration of the drug through the oral mucosa. Preferably, the effervescent agent is provided in an amount of about 5% to about 95% by weight, based on the weight of the final tablet, and more preferably in an amount of about 30% to about 80% by weight. 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 "blowing agent" includes compounds that release gas. Preferred effervescent agents release gas by a chemical reaction that occurs when the effervescent agent (effervescent couple) is exposed to water and / or saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source with a carbon dioxide source such as alkali carbonate or bicarbonate. The general reaction of these two compounds produces carbon dioxide gas on contact with water or saliva. Such materials that are activated by water will disintegrate the tablet when exposed to water at an earlier time, and will generally be retained in an anhydrous state with little or no absorption of water, or in a stable hydrated form. There must be. The acid source can be any that is safe for human consumption, and generally is an edible acid, for example, acids and hydrogens such as citric, tartaric, malic, fumaric, adipic, and succinic acids. Compound antacids. The carbonate source preferably includes dried and sold carbonates and bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate and the like. Includes 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 a reaction that forms carbon dioxide. Reactants that release oxygen or other gases that are safe for human consumption are also considered to be within the scope of the present invention. If the blowing agent comprises two mutually reactive components such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, the proportions of the components are preferably equivalent to provide equal equivalents. For example, if the acid used is diprotic, then twice as much mono-reactive carbonate base or equivalent amount of di-reactive base should be used to achieve complete neutralization. However, in other embodiments of the present invention, the amount of either the acid source or the carbonate source may exceed the amount of the other component. This may help to enhance the flavor and / or performance of tablets containing an excess of either component. In such a case, an extra amount of either component is allowed to remain unreacted.

  Such dosage forms may further comprise an amount of pH adjusting substance in addition to the amount required for foaming. In the case of a weakly acidic or weakly basic drug, the pH of the aqueous environment affects the relative concentrations of the ionized and non-ionized forms of the drug present in solution according to the Henderson-Hasselbach equation. there is a possibility. The pH solution in which the foaming couple is dissolved is slightly acidic due to the release of carbon dioxide. The pH of the local environment, e.g., the pH of the tablet and saliva in direct contact with the drug dissolved from the tablet, may include a pH-adjusting substance in the tablet that allows to control the relative ratio of the ionized and non-ionized forms of the drug. It can be adjusted by incorporating. In this manner, the dosage form can be optimized for each particular 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 subject's permissive limits) should be adjusted to the non-ionized form. Preferably, it is changed to a level that is convenient for the drug. Conversely, if the ionized form dissolves more easily, the local environment should be favorable for ionization.

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

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

  The dosage form of this embodiment of the invention may include one or more other ingredients to enhance absorption of the pharmaceutical ingredient through the oral mucosa and to improve the disintegration profile and organoleptic properties of the dosage form. It is preferable to include them. 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, "Mechanistic Studies on Efficient-Induced Permeability Enhancement" by Jonathan Eichman (1997), 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 may also include, in addition to the foaming agent, a suitable non-effervescent disintegrant. Examples of non-effervescent 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 It includes gums such as salt, agar, guar, locust bean, karaya, pectin, tragacanth and the like. Disintegrants may 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 sweetening or flavoring ingredients can be used. Sweeteners, flavoring ingredients, or combinations of sweeteners and flavoring ingredients can be used as well.

  Examples of binders which can be used include gum arabic, gum 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 acids, bentonite , Saccharides, invert sugar and the like. Binders can be used in amounts up to 60% by weight of the total composition, preferably about 10-40% by weight.

  Titanium dioxide, F.I. D. & C. Dyes suitable for foods such as dyes known as dyes, and natural coloring agents such as grape peel extract, beet red powder, β-carotene, annatto, carmine, turmeric, paprika and the like can be mentioned. The amount of colorant used may range from about 0.1% to about 3.5% by weight of the total composition.

  Flavors incorporated into the composition may be selected from synthetic and flavoring fragrances and / or natural oils, extracts from plants, leaves, flowers, fruits, and the like, and combinations thereof. Examples of these flavors include cinnamon oil, winter green oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave 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, etc. are also useful as perfumes. Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors, and mixtures thereof. The amount of flavoring may depend on several factors, including the organoleptic effect desired. 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. Excipient excipients can be used to facilitate tableting. Excipients also desirably aid 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 mouth of the subject and holding it under the tongue (for sublingual administration). The dosage form begins to disintegrate spontaneously due to moisture in the mouth. Disintegration, especially foaming, stimulates further salivation, which further enhances disintegration.

  While the formulations described above are also within the scope of the present invention, the most preferred orally dispersible solid pharmaceutical dosage form according to the present invention comprises an open matrix network retaining a pharmaceutically effective peptide and desmopressin, The 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 known from GB-A-1548022, see that patent for further details. The pharmaceutical dosage form of the present invention is rapidly disintegrable with water. "Rapidly disintegrates" means that the molded article disintegrates in water within 10 seconds. Preferably, the molded product disintegrates (dissolves or disperses) within 5 seconds. Disintegration time is measured in a manner similar to the Disintegration Test for Tables, British Pharmacopoeia (BP) 1973. This method is described in GB-A-1548022, and its outline is shown below.

Device No. at bottom end to form basket 1. A glass or suitable plastic cylinder 80-100 mm long, about 28 mm inside diameter, 30-31 mm outside diameter fitted with a rust-proof wire mesh disk according to the sieve requirements of 70.
A flat-bottomed glass cylinder having an inner diameter of about 45 mm and containing water at a temperature of 36 ° C to 38 ° C and a depth of 15 cm or more.
The basket is suspended from the center of the cylinder so that the basket rises and falls repeatedly in a constant fashion, with the net jumping slightly out of the water at the highest position and the upper edge of the basket remaining slightly above the water surface at the lowest position

Method A single molding is placed in a basket and the basket is raised and lowered in such a way that a complete raising and lowering movement 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. After 10 seconds no such particles should remain.

  The term "open matrix network" means a network of a water-soluble or water-dispersible carrier material with interspersed interstices. The open matrix network of the carrier material is generally of low density. For example, the density may be in the range 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 above-mentioned preferred limits of the density of the matrix network. An open matrix network, similar in structure to a solid foam, allows liquid to penetrate into the product through gaps and penetrate into the interior. Penetration by the aqueous medium exposes the carrier material, both inside and outside the product, to the action of the aqueous medium, causing the network of carrier material to rapidly collapse. The open matrix structure is porous and enhances the disintegration of the product as compared to conventional solid molded pharmaceutical dosage forms such as tablets, pills, capsules, suppositories and vaginal suppositories. Rapid disintegration causes a rapid release of the active ingredient 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 that can be rapidly disintegrated. It may be a material that can be dispersed in water or water. The use of a water-soluble material as a carrier is preferred, as the water-soluble material causes the most rapid matrix breakdown when the product is placed in an aqueous medium. Particularly advantageous carriers can be formed from polypeptides such as gelatin, especially gelatin, for example, which has been particularly hydrolyzed by heating in water. For example, the gelatin can be partially hydrolyzed by heating an aqueous solution of the gelatin, for example, in an autoclave at about 120 ° C. for up to 2 hours, for example, for about 5 minutes to about 1 hour, preferably for about 30 minutes to about 1 hour. The 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.

  Gelatin from mammals can also be used, but it has an unpleasant taste and thus masks the taste of gelatin in addition to any sweeteners and flavors needed to mask the taste of the active ingredient The use of sweeteners and flavors for In addition, the heating step required with the use of mammalian gelatin increases processing time and heating costs, thereby increasing the overall cost of the process. Therefore, especially for desmopressin, the use of fish gelatin, especially non-gelling fish gelatin, is preferred. See WO-A-0061117 for further details.

  Instead of partially hydrolyzed gelatin or fish gelatin, other carriers, such as hydrolyzed dextran, polysaccharides such as dextrins and alginates (eg sodium alginate), or the carriers mentioned above with one another or with polyvinyl alcohol , A mixture with other carrier materials such as polyvinylpyrrolidone or gum arabic. Instead of gelatin, modified starch 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 oils, gums, alcohols, petrolatum (petroleum jelly), and the like.

  The pharmaceutical dosage form of the present invention may be in the form of a molded product. They can incorporate other ingredients besides the active ingredient (s). For example, the pharmaceutical dosage forms of the present invention can incorporate pharmaceutically acceptable auxiliaries. Such adjuvants include, for example, colorants, flavors, preservatives (eg, bacteriostats), and the like. US-A-5188825 teaches that a water-soluble active agent should be bound to an ion exchange resin in order to form a substantially water-insoluble active agent / resin complex. Can also be performed here (see US-A-5188825 for further details), but in the course of the present invention, water-soluble peptides such as desmopressin do 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 invention. Thus, such dosage forms do not include an ion exchange resin. Desmopressin is not hydrophobic, but in the case of hydrophobic peptides, a surfactant may be present as taught in US Pat. No. 5,827,541 (see the patent for further details). . In the case of peptides with an unpleasant taste (without 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 free bases, as taught by US-A-5,838,875 and US-A-5,837,287. And the method disclosed in U.S. Pat. No. 5,976,577, wherein prior to lyophilization, the uncoated or coated grit of the pharmaceutically active substance (s) suspended in the carrier material is cooled, A method of reducing viscosity and minimizing the release of active substance during processing, and further minimizing unpleasant taste from peptides beyond the point of disintegration of the dosage form in the mouth (for further details see the patent ).

  In the case of insoluble or poorly soluble peptides having a large particle size, as disclosed in US Pat. No. 5,631,023, especially when the carrier is formed from gelatin, xanthan gum can act as a gelatin flocculant, 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 of those having about 2 to 12 carbon atoms, as taught by WO-A-9323017. Or more than one amino acid may be present. In this formulation, the preferred amino acid is glycine, while the preferred matrix former is gelatin and / or pectin, and in a particularly preferred embodiment, 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 in a manner as described in GB-A-1548022, which comprises sublimating the solvent from a composition comprising a solution of the drug substance and the carrier material in a solvent, wherein the composition comprises The object is in a solid state in the mold.

  Sublimation is preferably carried out by freeze-drying a composition comprising the active ingredient and a solvent solution of the carrier material. The composition may include further components as previously mentioned. The solvent is preferably water, but can include co-solvents (such as alcohols such as tert-butyl alcohol) to improve the solubility of the chemical. The composition can also include a surfactant, such as Tween 80 (polyoxyethylene glycol (20) sorbitan monooleate). Surfactants can help prevent the lyophilized product from sticking to the mold surface. Surfactants may 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 in the range of 4-5, for example 4.5 or 4.8. PH adjuster. Although citric acid is the preferred pH adjuster, other adjusters including hydrochloric acid, malic acid can be used. Such non-volatile pH adjusters are not removed by lyophilization or other sublimation treatment and may be present in the final product.

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

  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 the material 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. Laminates 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 of using such a mold, the mold is cooled with a cooling medium (eg, liquid nitrogen or solid carbon dioxide). Once the mold has cooled, a predetermined amount of water, including the carrier material, the active ingredient and any other desired ingredients, is supplied to the well (s). Once the contents of the well (s) are frozen, the mold is subjected to reduced pressure and, if desired, controlled heat is applied to aid in sublimation. The pressure may be less than about 4mmHg. GB-A-1548022 teaches that it is preferable to employ a pressure of less than 0.3 mmHg, for example 0.1 to 0.2 mmHg. The lyophilized product can be removed from the mold recess and stored for future use, for example, in an airtight jar or other suitable storage container. 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 pharmaceutical dosage forms according to the present invention is described in GB-A-2111423 (for further details see the patent). The method comprises filling a mold with a composition comprising a predetermined amount of active ingredient and a partially hydrolyzed gelatin solution, freezing the composition in the mold by 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 mold sidewall or walls are diverged outwardly 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 may comprise freezing a composition comprising a first solvent solution of a water-soluble or water-dispersible carrier material inert to the active ingredient; Sublimating the first solvent from the product to produce a product having a network of carrier components, 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, and can be prepared by a method as described in GB-A-2114440.

  Alternatively or additionally, the pharmaceutical dosage form of the invention comprises introducing a droplet of liquid medium directly below the surface of a cooling liquid maintained at a temperature below the freezing point of the liquid medium. 2111184, wherein the cooling liquid is immiscible and inert with respect to the liquid medium, the liquid droplets float up in the cooling liquid towards its surface and freeze. It has a greater density than both the liquid medium and the resulting frozen particles so as to form spherical particles. The frozen spherical particles can be collected at or near the top surface of the cooling liquid. See GB-A-2111184 for further details.

  The dosage form according to the 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, below the tongue (sublingual).

  According to a second aspect of the present invention, there is provided a medicament, in particular a dosage form as described above for use in postponement, 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, wherein the method comprises administering to a patient And the administration of an effective and generally non-toxic amount of desmopressin across the sublingual mucosa, for example, in the form described above. Any other disease or condition treatable or preventable with desmopressin can be similarly addressed by the means of the present invention. The present invention therefore extends to the use of desmopressin in the manufacture of a sublingually absorbable pharmaceutical formulation. The invention also extends to a pack containing a pharmaceutical dosage form capable of sublingual absorption of desmopressin together with instructions for placing the dosage form sublingually in the patient.

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

  In addition to desmopressin, other peptides can be formulated in 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 present invention there is provided a solid pharmaceutical dosage form, e.g., for oral administration, wherein the pharmaceutical dosage form comprises a pharmaceutically effective peptide, and an open matrix network carrying 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 an oral vaccine in a rapidly dissolving dosage form, but there is no disclosure of a pharmaceutically effective peptide which retains its activity after administration. Experimental studies of WO-A-9921579 only show the presence of IgA antibodies to tetanus toxoid in saliva following administration of tetanus toxoid by means of an adjuvant rapid lysing 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 be directly effective themselves, or they may have one or more active metabolites, ie, they are pro-active to the underlying or truly active essential components. Drag is fine. The peptide can have, for example, from 2 to 20, preferably from 5 to 15 amino acid residues (the L-isomer is generally predominant, at least a portion of which is the D-isomer) ). Peptides may be linear, branched or cyclic and may contain natural residues or substituents, or residues or substituents not commonly or not 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- Thr-Phe-GABA) somatostatin analogs containing, Met ⁵ - enkephalin and Leu ⁵ - enkephalins including enkephalin, atosiban (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-hydrooro _{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 Where ILys is N (8) -isopropyl lysine, 4Aph is 4-aminophenylalanine and Cbm is a carbamoyl group), and US Pat. No. 5,925,730 and US Pat. Other disclosed GnRH antagonists, and vasopressin analogs such as desmopressin. It is particularly preferred to formulate agonists of naturally occurring active peptides, such as the peptides described above, in accordance with the present invention, as the agonist is effective at lower doses than the antagonist.

  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 invention extends to the use of the peptide in the manufacture of a dosage form as described above for treating or preventing 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 patient an effective and generally non-toxic amount of the peptide in the above-described dosage form. Including.

Analysis and Application of Low Dose As indicated above, the doses and plasma / plasma / serum concentrations of desmopressin that are today recommended and the resulting plasma / plasma / serum levels are 5-40% are: It is therapeutically effective and in some cases safer against certain disease states, such as CDI, PNE, and additional clinical signs requiring pharmacological levels of urine.

  Clinical observation of adult boys and girls treated with desmopressin for a condition known as nocturia, which causes frequent nocturia, suggests that lower doses of desmopressin are desirable. In this patient population, standard nasal and oral administration of desmopressin unexpectedly caused hyponatremia, a condition in which plasma / plasma / serum sodium was reduced to abnormally low levels with a high incidence. Provoked. Hyponatremia can result in stroke, 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 suggested that the pharmacodynamic effect on urine concentration was unnecessarily high resulting in excessive duration. 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 concentration of desmopressin in plasma / plasma / serum after administration of the pharmaceutical composition of the present invention is preferably from about 0.1 pg / mL to about 10.0 pg / mL, more preferably about 0.1 pg / mL. It ranges from 5 pg / mL to about 5.0 pg / mL. These amounts and ranges of desmopressin include, but are not limited to, intravenous (bolus, injectable), subcutaneous (bolus, injectable, depot), intranasal, transmucosal, as outlined below. (Buccal and sublingual, for example, orodispersible tablets, wafers, films and foams, conjunctiva (ophthalmic solution), rectum (suppository, enema)), transdermal (passive patch, gel, cream, ointment or It can be administered by any method known in the art, including iontophoresis) or intradermally (bolus, injection, depot). In addition, pharmaceutical compositions containing desmopressin in an amount that provides desmopressin concentrations in plasma / plasma / serum as described above can be prepared by the methods and the use of the carrier, or by any other method known in the art.

The dosage ranges of desmopressin outlined above can provide adequate antidiuretic effects when administered by various routes as summarized in the examples below.

  Low-dose desmopressin can be used to treat central diabetes insipidus, prevent primary nocturnal enuresis, prevent nocturia, and treat clinical disorders related to nocturia, including but not limited to sleep disorders It may be an effective treatment regimen for the prevention of incontinence (tension, urgency, etc.) and for clinical signs such as postponement of urination when awake.

  Specific formulations of desmopressin can also be created that enhance absorption and enhance its systemic bioavailability. These formulations produce an additional pharmacological effect at each point along the dose response curve, thereby amplifying the activity of desmopressin even at low doses.

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

Example 1 200 μg desmopressin oral dispersible dosage form Spray-dried fish gelatin (4 g) and mannitol (3 g) are placed in a glass beaker. Then, purified water (93 g) is 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 into each of a series of blister pockets having a preformed pocket diameter of about 16 mm. The blister stack may include 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 then the frozen dosage unit is 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, raising the shelf temperature from the initial 10 ° C. to + 20 ° C. Prior to removal, the dose units were examined for moisture by dry trace and by a pressurized moisture test.

Thus, according to the general procedure set forth in Example 1 of WO-A-0061117, an orodispersible dosage form of desmopressin is prepared 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 Orally 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 Orally 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 Orally Dispersible Dosage Form Desmopressin Dosage Form, Orally Dispersible Dosage Form According to the general procedure set forth in Example 1 of WO-A-0061117, using the following ingredients per unit dosage form: 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 Orally 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 Orally 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. Solutions The following ingredients were used to routinely prepare injectable formulations of desmopressin.
Desmopressin (PolyPeptide Laboratories, Sweden)
4mg
9mg sodium chloride
(National Corporation of Swedish Pharmacies, Sweden)
Hydrochloric acid (1N) (Merck, Germany) Up to pH 4 Water for injection Up to 1 ml in total volume

(Comparative Example 2) 200 µg desmopressin conventional tablet A tablet containing the following components was prepared using a usual wet granulation method.
Desmopressin (PolyPeptide Laboratories, Sweden)
200 μg
Lactose (Pharmatose 150M, DMV, Netherlands) 120mg
Potato starch (Lykeby AB, Sweden) 77mg
1.8mg PVP (Kollidon 25, BASF, Germany)
Magnesium stearate (Peter Green, Germany) 1mg
Liquid for granulation (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 Design In this study, 24 healthy non-smoking male volunteers were enrolled. The study was designed as a one-center, open-labeled, randomized, balanced, four-way crossover Phase I study. Each subject received, in randomized order, desmopressin as a 200 μg, 400 μg and 800 μg orally dispersible dosage form (Examples 4, 5 and 6, respectively) sublingually 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 orodispersible tablets. Subjects were allowed to brush in the morning before dosing, without using toothpaste.

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

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

Pharmacokinetic Analysis Plasma desmopressin concentrations were determined using commercially available software WinNonlin ™ Pro, ver. Analyzes were performed on individual volunteers in each treatment group 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 NCA analysis and descriptive statistics for concentration. Values below the LOQ that were not followed by values above the LOQ were excluded from the NCA analysis and set to zero in the descriptive statistics for concentration.

Pharmacokinetic analysis results i. v. After administration, the steady state mean distribution volume (Vss) was 29.7 dm ³ . The average clearance was calculated to be 8.5 dm ³ / hr, and the average elimination half-life was determined to be 2.8 hours. Maximum plasma concentrations of desmopressin after oral administration were observed between 0.5 and 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 eliminated with a mean elimination half-life ranging from 2.8 to 3.0 hours. Bioavailability was determined to be 0.30% with a 95% confidence interval of 0.23-0.38%.

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

Comparative Example 4 Bioavailability of desmopressin administered according to Comparative Examples 2 and 3 In this study, designed as an open label, single dose, three-way crossover study, 36 healthy male volunteers (Caucasians) , Blacks and Hispanics). To each subject, in randomized order, 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 administration (Comparative Example 1) Was administered as 2 μg.

  i. v. Following administration, the mean elimination half-life was determined to be 2.24 hours. The maximum plasma concentration of desmopressin after oral administration 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. Bioavailability was determined to be 0.13% (2 × 100 μg) or 0.16% (1 × 200 μg).

Example 8 Crossover Study Examining the Antidiuretic Effect of Three Levels of Low-Dose Desmopressin In the following example, a two-hour intravenous infusion in hyperhydrated, healthy, non-smoking male and female volunteers was performed. A study showing the antidiuretic effect of three levels of low dose desmopressin is described. Briefly, this is an open-label, cross-over study of eight healthy, hyperhydrated, non-smoking male and female volunteers 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 two day (48 hour) washout period was observed between doses.

  The study evaluated eight subjects, five boys and three girls. Their weight was 85.9, 65, 80.9, 63.3, 72.5, 67.6, 63.5, and 54.5 kg. The average weight of the eight subjects was 69.15 kg, which is very close to the standard 70 kg body weight estimate based on desmopressin dosage and blood levels in this study. On the first day of the study (first day of dosing), subjects were hyperhydrated by drinking a volume of water equal to 1.5% of body weight and maintaining hyperhydration by replacing urine output with water intake. . In this study, 0.5, 1.0 and 2.0 ng / kg desmopressin in 100 mL of sterile saline (0.9%) (USP injection) was used. Three levels of desmopressin infusion (one each of the above concentrations) were administered at a constant rate of I.H. V. It was 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 termination of desmopressin infusion, subjects were voided every 20 minutes and monitored until three consecutive urine collections measured voiding levels greater than 10 mL / min. At this point, hyperhydration was discontinued. Urine osmolality was measured by collecting urine as a basal amount 20 minutes before infusion and every 20 minutes until 6 hours after the start of infusion. The specific gravity of urine was also measured. Plasma / serum sodium and plasma / serum osmolality were measured before dosing and at 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. The same 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 exit screening for laboratory signs of serious signs, blood and urine.

Study criteria include urine output 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. Statistical analysis was descriptive and all statistical hypotheses were tested for research purposes. The following items were examined. Each subject is evaluated using three different osmolality levels (150 mOsm / kg, 200 mOsm / kg and 400 mOsm / kg) with duration of action or time from "onset" to "end" of action as a limit. did. First, the duration of action is determined from the onset of action (ie, the first time the urine osmolality was less than 150 mOsm / kg after dose administration) to the end of action (urine osmolality of 150 mOsm / kg). / Kg / day, and the first subsequent time, if not the last observation point, will be confirmed in the next interval). The second and third evaluations used 200 mOsm / kg and 400 mOsm / kg as the threshold levels for "onset" and "end" of action, respectively. Subjects without an "end" of action for this definition were deleted when their urine output returned to basal (> 10 mL / min) and / or when the hyperhydration procedure was stopped. The total duration of action was evaluated for each treatment group using the non-parametric Kaplan-Meier method. Various means for estimating the duration of action will provide lower and upper bounds on the true probability, ie the probability of desmopressin action as a function of time. In addition, duration of action is indicated using mean, SD, median, minimum and maximum values for each treatment group. The dose-response relationship between duration of action and dose was investigated using appropriate linear or non-linear models. From the individual concentration versus time curves of desmopressin, the pharmacokinetic parameters: AUC (area under the plasma concentration-time curve to infinity), C _max (maximum plasma concentration observed), t _max (C _max after administration and Time) CL (total systemic clearance) V _z (volume of distribution in terminal phase), AUC _t (area under the plasma concentration-time curve from time 0 to time t), λ _z (log 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 (terminal half-life) were derived.

Summary of Results All three levels of dose of desmopressin (IV infusion) have measurable dose-response levels of increased urine concentration (osmolality) and decreased urine output. Produced a 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 a 2 hour infusion at each dose level. Basal mean urine osmolality was 55.8, 55.8 and 55.6 for 0.5, 1.0 and 2.0 ng / kg doses, respectively. Maximum urine osmolality was 206.0, 444.7 and 587.2 at 2 hours for doses of 0.5, 1.0 and 2.0 ng / kg, respectively. Mean minimum urine output (mL / min) also appeared at the end of the 2 hour infusion for each dose level. Basal minimum urine output was 18.6, 16.6 and 16.9 mL / min for doses of 0.5, 1.0 and 2.0 ng / kg, respectively. The mean minimum urine 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 and excretion of urine of each subject and the average value at each time.

  As shown in Tables 1 to 6 and FIGS. V. Low doses of desmopressin administered over 2 hours as an infusion produced a significant antidiuretic effect in a hyperresponsive normal subject in a dose responsive manner. These doses and estimated plasma / serum concentrations of desmopressin are much more than an order of magnitude lower than the stated recommended and clinical practice amounts today. 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 potentially new clinical signs for desmopressin. Safety and tolerance were excellent.

  The results of this study demonstrate the low-dose hypothesis for desmopressin and allow 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 indications is based on the pharmacological antidiuretic effect of desmopressin, which results in the production of smaller volumes of more concentrated urine. In patients with central diabetes insipidus, the pituitary gland does not produce or produces very little vasopressin, a natural antidiuretic hormone. This deficiency causes the production of large amounts of very dilute urine, which can lead to dehydration and severe metabolic abnormalities unless the patient consumes 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 (sleeping urine), the antidiuretic effect of desmopressin reduces nocturnal urine volume and reduces the amount of urine that the urinary bladder must retain, thereby reducing or eliminating enuresis I do.

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

  In patients with various incontinences (tonicity, urgency, etc.) that are often associated with urinary bladder abnormalities resulting from surgery, childbirth, and aging, the bladder cannot hold even normal amounts of urine. Low volume threshold for urination, high risk of unintentional urination (incontinence). The antidiuretic effect of desmopressin reduces urine production and delays crossing with an abnormally low voiding volume threshold in these patients, thus allowing postponement.

  In all of the above clinical indications, or in the medical use of desmopressin, its pharmacological antidiuretic effect resulting in reduced production of more concentrated urine is the mechanism of therapeutic efficacy. This clinical study shows that desmopressin can produce this essential 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.

Embodiments of the present invention include the following.
[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 of desmopressin.
[3] The pharmaceutical composition of [1], comprising about 0.05 μg to about 10 μg of desmopressin.
[4] The pharmaceutical composition of [1], comprising about 0.1 μg to about 20 μg of desmopressin.
[5] The pharmaceutical composition of [1], configured for intravenous, subcutaneous, transmucosal, transdermal, or intradermal delivery.
[6] The pharmaceutical composition according to [1], which is in the form of a dispersible solid in the mouth.
[7] The pharmaceutical composition according to [1], further comprising an open matrix network, wherein the open matrix network comprises a water-soluble or water-dispersible carrier material that is inactive against desmopressin.
[8] A pharmaceutical composition comprising desmopressin and a pharmaceutically acceptable carrier, wherein the composition comprises a stationary phase ranging from about 0.1 picograms of desmopressin per mL of plasma / serum to about 10.0 picograms of desmopressin per mL of plasma / serum. A pharmaceutical composition that is effective in establishing a high plasma / serum desmopressin concentration.
[9] The method according to [8], wherein the stationary plasma / serum desmopressin concentration ranges from about 0.5 picograms of desmopressin per mL of plasma / serum to about 5.0 picograms of desmopressin per mL of plasma / serum. Pharmaceutical composition.
[10] The pharmaceutical composition of [8], comprising about 0.5 ng to about 2000 ng of 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], configured for intravenous, subcutaneous, transmucosal, transdermal, or intradermal delivery.
[14] An article of manufacture comprising a packaging material and a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition comprises hemophilia, von Willebrand's disease, incontinence, primary nocturnal enuresis (PNE). Therapeutically effective to treat or prevent nocturia, or central diabetes insipidus, wherein the packaging material allows the pharmaceutical composition to treat the hemophilia, von Willebrand disease, incontinence, primary nocturnal enuresis A label indicating that the composition can be used to treat or prevent PNE, nocturia, or central diabetes insipidus, wherein the pharmaceutical composition comprises 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier A product comprising
[15] A method for treating or preventing a disease or condition treatable or preventable by desmopressin, which comprises administering to a patient a therapeutically effective amount of a medicament comprising 0.5 ng to 20 μg of desmopressin and a pharmaceutically acceptable carrier. A method comprising 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 [15] ].
[17] inducing an antidiuretic effect in the patient, comprising administering to the patient a daily effective amount 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 has a disease selected from the group consisting of von Willebrand disease, incontinence, primary nocturnal enuresis (PNE), nocturia, or central diabetes insipidus; ].

Claims (7)

100 Ng～2000ng of desmopressin and intranasal, sublingual, buccal, transmucosal, or comprises a pharmaceutically acceptable carrier are configured for intradermal administration, of nocturia treatment or for the prevention Pharmaceutical composition.   The pharmaceutical composition according to claim 1, wherein the nocturia is adult nocturia. 3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is configured for intranasal administration. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable carrier is configured for sublingual administration. 3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is configured for buccal administration. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable carrier is configured for transmucosal administration. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable carrier is configured for intradermal administration.

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