Desmopressin in an orodispersible dosage form

The invention relates to pharmaceutical dosage forms of desmopressin acetate.

Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is an anti-diuretic analogue of vasopressin. It is commercially available as an acetate, in tablet form or as a nasal spray, and is commonly prescribed for, among other things, delaying urination, urinary incontinence, primary nocturnal enuresis (PNE) and nocturnal urination, including central diabetes insipidus .

While existing desmopressin formulations meet patient requirements, there is still room for improvement. Tablets are often preferred by patients because of their ease of use, discretion and lack of uncertainty about correct administration. However, the intake of tablets usually requires a glass of water or another drink, which is a problem since fluid intake should be limited when treating desmopressin, and the patient guidance is much clearer when no water is used at all. Moreover, the bioavailability of desmopressin when taken as a tablet is about 0.1% compared to intravenous injection, a figure that clearly indicates a room for improvement.

Nasal administration leads to higher bioavailability. but is less preferred by patients. In addition, intranasal administration may adversely affect the cilia so that viruses and bacteria can more readily penetrate the mucosa.

Sublingual preparations of desmopressin have also been proposed. Grossman and others. Br. Med. J. 1215 (May 17, 1980) reported the administration of desmopressin in a sublingual lozenge of undefined composition. In the same year, Lachi and others. Int. J. Clin. Pharm. Ther. Tox. 18 (12) 63-68 (1980) reported the administration of 30 μg desmopressin in 200 mg sublingual tablets containing sucrose, potato starch, stearin, ethanol (in rectified form), white gelatin, distilled water and cocoa powder. However, WO-A-8502119 states:

The so-called sublingual tablet is also questionable as it requires a relatively long dissolution time and is dependent on the salivation of the patient. [WO-A-8502119. p. 2. lines 4-6]

Fjellestad-Paulsen et al. Clin. Endocrinol. 38 177-82 (1993) administered a sublingual liquid formulation of desmopressin in the form of a nasal spray which overcome the problems outlined above for the sublingual tablet. However, the authors reported that no desmopressin was detected in the blood following sublingual administration of the liquid.

It has now been found that desmopressin can be administered as a solid, orodispersible dosage form that provides increased bioavailability compared to conventional oral desmopressin tablets.

In a first aspect, the invention provides a pharmaceutical dosage form of desmopressin acetate which disperses in the oral cavity within 10 seconds.

Typically the dosage form will be solid. It can quickly disperse in the oral cavity, e.g. within 10, 5, 2 s or even within 1 s, with increasing preference in this direction. Such dosage forms are referred to as "orodispersible". The dosage form will usually contain a suitable carrier, which will be pharmaceutically acceptable (or veterinarily acceptable for administration to animals).

The daily dose of desmopressin, measured as free base, will typically be in the range of 0.5 or 1 µg to 1 mg per dosage form. In one preferred dose range, the dose will typically be in the range of 2-800 µg per dosage form, preferably 10-600 µg. In particular, relatively low doses are also contemplated, e.g. 0.5-75 µg, preferably 0.5 or 1 to 50 µg. When one dose is administered daily, as is usual for PNE and nighttime urination, this will usually be a dosage in the form of a dosage form. When the daily dose is administered in two or more doses, as will usually be the case with central diabetes insipidus, the amount of active ingredient in the dosage form will be correspondingly reduced.

Other active substances, peptide or non-peptide, may also be present.

The pharmaceutical dosage forms of the invention are adapted to deliver the active ingredient to the oral cavity. The active ingredient can be absorbed through the sublingual mucosa and / or otherwise from the oral cavity (e.g., via the buccal and / or gingival mucosa) and / or from the gastrointestinal tract for distribution throughout the body.

PL 208 482 B1

Many formulations suitable for delivering other active ingredients for absorption from the oral cavity are known. Such formulations may be useful in the invention. These include buccal disintegrating solid preparations or preparations containing the active ingredient, sugar in the form of lactose and / or mannitol, and 0.12 - 1.2% by weight, based on solids, agar, with a density of 400 - 1000 mg / ml and of sufficient handling strength, which in practice may be sufficient strength to withstand removal from the blister pack without disintegration. Such formulations and methods for their preparation are disclosed in US A-5,466,464, where additional details can be found.

Other formulations known to deliver active ingredients for absorption from the oral cavity are the dosage forms disclosed in US-A-6,024,981 and US-A-6,221,392. These are hard, compressed, rapidly dissolving dosage forms suitable for direct administration into the oral cavity, containing: an active ingredient and a matrix containing a non-directly compressible filler and a lubricant, the dosage form being adapted to dissolve rapidly in the mouth of the patient and thereby to release the active ingredient, and having a brittleness of about 2% or less when tested in accordance with USP and further the dosage form has a hardness of at least about 15 Newtons (N), preferably 15-50 N. US-A-6,024,981 and US-A-6221392 disclose additional details and characteristics of these dosage forms and methods for their preparation.

The use of non-directly compressible fillers eliminates the need for many of the usual processing steps such as granulation and / or the need to purchase more expensive pre-granular compressible fillers. At the same time, a balance between performance and stability is maintained in the resulting dosage form. It is strong enough to be obtained in the usual way by direct compression. It is strong enough to be stored or packed in the bulk. At the same time, it quickly dissolves in the oral cavity while minimizing the unpleasant sensations characteristic of conventional disintegrating tablets.

Other known formulations for the delivery of active ingredients for absorption from the oral cavity are the dosage forms disclosed in US-A-6,200,604. containing an orally administered drug in combination with an effervescent agent used as a penetration enhancer, influencing the penetration of the drug through the buccal, sublingual and gingival mucosa. In an embodiment of the invention, the drug is desmopressin which is administered through the sublingual membrane in some embodiments. In the dosage forms of this embodiment of the invention, the effervescent agents may be used alone or in combination with other penetration enhancers, leading to an increase in the rate and extent of absorption of the active ingredient from the oral cavity.

In one embodiment, the invention provides a solid oral tablet as a dosage form suitable for sublingual administration. Excipients-fillers can be used to facilitate tabletting. Conveniently, the filler will also assist in the rapid dissolution of the dosage form in the oral cavity. Non-limiting examples of suitable fillers include: mannitol, dextrose, lactose, sucrose, and calcium carbonate.

As described in US-A-6,200,604 tablets may be prepared by direct compression, wet granulation or any other technique for making tablets. The dosage form can be administered to a human or other mammal by placing the dosage form in the mouth of the subject and holding it in the mouth, under the tongue (for sublingual administration). The dosage form begins to disintegrate spontaneously on exposure to moisture in the mouth. The disintegration, and especially the effervescence, stimulates additional salivation, which further enhances the breakdown.

The pharmaceutical dosage forms of the invention comprise desmopressin acetate and an open matrix network containing desmopressin and fish gelatin, the open matrix network being a water-soluble or water-dispersible matrix material, inert towards desmopressin.

Pharmaceutical dosage forms containing open matrix networks are known from GB-A-1548022 where additional details can be found. The pharmaceutical dosage forms of the invention can disintegrate rapidly on exposure to water. "Rapid disintegration" means that the shaped articles disintegrate in water within 10 seconds. Preferably the shaped article disintegrates (dissolves or disperses) in 5 seconds, or even within 2 seconds, or in 1 s or faster. It measures the time of disintegration

The method is analogous to the Tablet Disintegration Test, BP 1973. The procedure is described in GB-A-1548022 and is outlined below.

The camera

Tube of glass or a suitable plastic, 80 - 100 mm long, internal diameter approximately 28 mm and external diameter 30 - 31 mm and fixed at the lower end to form a basket with a disc of rust-resistant wire mesh meeting the requirements for sieve No. 1.70.

Glass cylinder with a flat base and an inside diameter of approximately 45 mm, containing a layer at least 15 cm thick of water at a temperature of 36-38 ° C.

The basket is suspended from the center of the roller in such a way that it can be evenly raised and lowered several times, so that in the highest position the strainer is just below the water surface. and in the lowest position of the basket, it protruded just above the water surface.

Method

Place the shaped article in the basket and then lift it up and down in such a way that the complete up and down cycle is repeated at a frequency of 30 times per minute. The shaped articles disintegrate when no particle is found above the mesh that cannot easily pass through it. No such particle should remain after 10 seconds.

The term "open matrix network" denotes a network of water-soluble or water-dispersible support material with scattered fractures. An open matrix network of carrier material is generally of low density. For example, the density may be 10-200 mg / cm³ e.g. 10 - 100 mg / cm³preferably 30-60 mg / cm³. The density of the shaped article may be influenced by the amount of active ingredient or other ingredients incorporated into the article and may fall outside the aforementioned preferred matrix network density limits. An open matrix network with a structure similar to solid foam allows the liquid to enter the product through the gaps and penetrate into its interior. Penetration of the liquid medium exposes the carrier material both inside and outside the product to the aqueous medium, whereby the web of the carrier material quickly disintegrates. The open matrix structure is porous in nature and facilitates the disintegration of the product compared to conventional solid shaped pharmaceutical dosage forms such as tablets, pills, capsules, suppositories and pessaries. Rapid disintegration results in a rapid release of the active ingredient carried through the matrix.

The carrier material used in the product of the invention may be any water-soluble or water-dispersible material that is pharmacologically acceptable or inert to the chemical and that is capable of forming a rapidly disintegrating open matrix network. Preferably, a water-soluble material is used as the carrier, as this causes the matrix to disintegrate faster when the product is placed in an aqueous medium. A particularly advantageous carrier can be made of polypeptides. such as gelatin, especially gelatin, especially which is particularly hydrolyzed. e.g. by heating in water. Gelatin can be partially hydrolyzed by heating a solution of gelatin in water, e.g., in an autoclave at about 120 ° C, for a period of up to 2 hours, e.g., about 5 minutes to about 1 hour, preferably for about 30 minutes to about 1 hour. hours. Hydrolysed gelatin is preferably used at a concentration of about 1-6% or 8% w / v, most preferably 2-4%. e.g. about 3% or 4-6%. e.g. about 5%. As is evident from the accompanying examples, these concentrations apply to the entire formulation prior to removal of water, e.g. by freeze-drying.

The pharmaceutical dosage forms of the invention may be in the form of shaped articles. They may contain ingredients other than the active ingredient (s). For example, the pharmaceutical dosage form of the invention may contain pharmaceutically acceptable auxiliaries. Such auxiliaries include, for example, coloring agents, flavorings, preservatives (e.g., bacteriostatic agents), etc. US-A-5,188,825 discloses that water-soluble actives should be bonded to an ion exchange resin to form a substantially water-insoluble active substance / resin complex; although such disclosure can be made in this case (see US-A-5188825 for more details), it has been found in an embodiment of the invention that water-soluble peptides such as desmopressin can be formulated into solid dosage forms of the invention without the need to bind them to an ion exchange resin. Therefore, such dosage forms may be free of ion exchange resin. In the case of hydrophobic peptides to which desmopressin does not belong, it may be present

PL 208 482 B1 as a surfactant as disclosed in US-A-5,827,541 where more details can be found.

All excipients are selected to be pharmaceutically acceptable.

The pharmaceutical dosage forms of the invention can be prepared according to the method described in GB-A-1548022, which comprises sublimation of a solvent from a composition comprising the pharmaceutical substance and a solution of the carrier material in a solvent, the composition being in solid form.

Sublimation is preferably carried out by freeze-drying the composition containing the active ingredient and a solution of the support material in a solvent. The composition may contain additional ingredients such as those listed above. The solvent is preferably water, although it may contain a co-solvent (such as an alcohol, e.g. t-butyl alcohol) to improve the solubility of the chemical components. The composition may also contain a surfactant, e.g. Tween 80 (polyoxyethylene (20) sorbitan monooleate). The surfactant can help prevent sticking of the freeze-dried product to the surface of the molds). It may also help disperse the active ingredient.

The mold may include a series of cylindrical or other shaped recesses, each of a size corresponding to the desired size of the shaped article. Alternatively, the cavity in the mold may be larger than the desired product such that, after freeze-drying the contents, the product may be cut into pieces of the desired size (e.g., thin wafers).

However, as described in GB-A-2111423, the mold preferably forms a recess in the sheet of foil material. The foil material may contain more than one depression. The foil material may be similar to the material used in conventional blister packs used to package oral contraceptive pills and similar drug forms. The foil material can e.g. be made of a thermoplastic material with recesses made by thermoforming. A preferred foil material is polyvinyl chloride foil. A laminated film material can also be used.

In one embodiment, the mold is a metal plate (e.g., aluminum plate) having one or more cavities. In a preferred method using such a mold, the mold is cooled with a cooling agent (e.g., liquid nitrogen or solid carbon dioxide). When the mold is cooled, a predetermined amount of the water-containing carrier material, the active ingredient, and any other desired ingredient is introduced into the recess (s). When the contents of the cavity (s) are frozen, the mold is pressurized and if necessary, heat is applied in a controlled manner to aid sublimation. The pressure may be less than about 4 mm Hg; GB-A-1548022 discloses the use of a pressure below 0.3 mmHg, e.g. preferably 0.1-0.2 mm. Frozen and dried products can then be removed from the cavities in the mold and stored for later use, e.g. in airtight jars or other suitable storage containers. Alternatively, the freeze-dried product can be sealed with foil material as described in GB-A-2111423.

A later devised process suitable for the preparation of pharmaceutical dosage forms according to the invention is described in GB-A-2111423 where more details can be found. The method includes filling a composition containing a predetermined amount of active ingredient and partially hydrolyzed gelatin into a mold, freezing the composition in a mold by passing a gaseous cooling agent over the mold, and then sublimating the solvent from the frozen composition to obtain a partially hydrolyzed gelatin network containing the active ingredient.

Alternatively or additionally, the pharmaceutical dosage forms according to the invention may be prepared by the method described in GB-A-2114440, comprising freezing the composition containing a solution in a first water-soluble or water-dispersible carrier material inert to the active ingredient, sublimating the first solvent from the frozen composition so as to obtain the product in the form of a network of carrier material, adding to the product a solution or suspension in a second, non-aqueous solvent containing a predetermined amount of the active ingredient, and allowing or causing the second solvent to evaporate. See GB-A-2114440 for more details.

The dosage forms according to the invention are characterized by increased bioavailability. They are intended for oral use and are highly suitable for this purpose. They dissipate quickly in the mouth and can e.g. be placed under the tongue (sublingual administration), or they can be placed on the tongue or against the cheek or on the gums.

PL 208 482 B1

The content of each of the documents cited in the description that is introduced as a literature source to the fullest extent permitted by law.

The following examples illustrate the invention.

Example 1 Oral Dispersible Dosage Form With 200 Pg Desmopressin

Spray dried fish gelatin (4 g) and mannitol (3 g) were added to a glass beaker. Purified water (93 g) was then added and the mixture was stirred with a magnetic stirrer until a solution was obtained. The pH was checked and, if necessary, adjusted to 4.8 with citric acid.

The Gilson pipette can then be used to dispense 500 mg of this solution into each of a series of pre-formed blister pockets approximately 16 mm in diameter. The blister laminate may contain PVC (polyvinyl chloride) coated with PVdC (polyvinylidene chloride). The dosage units are then frozen at -110 ° C in a freezing tunnel with a 3.2 minute residence time and the frozen units are then kept in the rising freezer for more than 1.5 hours at -25 ° C (± 5 ° C). C). The units are then freeze-dried overnight at an initial shelf temperature of 10 ° C with increasing the temperature to + 20 ° C. at a pressure of 0.5 mbar. Before discharging, the moisture content of the units can be checked by drying the sample and with a pressure hygrometer.

Thus, according to the general procedure given in Example 1 of WO-A-0061117, an orally dispersible dosage form of desmopressin was prepared using the following ingredients; per unit dosage form:

Desmopressin (PoliPeptide Laboratories, Sweden) 200 μg

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

Fish Gelatin USNF / EP 20 mg

Citric acid (if required) [pH adjuster] if needed to pH 4.8

Purified water [Removed during processing]

Example 2 Oral Dispersible Dosage Form With 400 Pg Desmopressin

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

Example 3 Oral Dispersible Dosage Form With 800 Pg Desmopressin

The procedure of Example 1 was followed except that the amount of desmopressin in a unit dosage form was 800 µg.

Example 4 Oral Dispersible Dosage Form With 200 Pg Desmopressin

According to the general procedure outlined in Example 1 of WO-A-0061117, an orally dispersible dosage form of desmopressin was prepared using the following ingredients, based on the unit dosage form:

Desmopressin (PoliPeptide Laboratories, Sweden) 200 μg

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

Fish Gelatin USNF / EP 10 mg

Citric acid (if required) [pH adjuster] if needed to pH 4.8

Purified water [Removed during processing]

Example 5 Oral Dispersible Dosage Form With 400 Pg Desmopressin

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

Example 6 Oral Dispersible Dosage Form With 800 Pg Desmopressin

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

Comparative Example 1. Intravenous Desmopressin Solution

The injectable desmopressin formulation was prepared in the usual manner with the following ingredients:

9 mg as needed for pH 4 as needed for 1 ml

<td> 200</td><td>μg</td>

<td> 120</td><td>mg</td>

<td> 77</td><td>mg</td>

<td> 1</td><td>8 mg</td>

<td> 1</td><td>mg</td>

Desmopressin (PoliPeptide Laboratories, Sweden)

Sodium chloride (National Corporation of Swedish Pharmacies, Sweden)

Hydrochloric acid (1N) (Merck, Germany)

Water for injection

Comparative Example 2. Plain tablet with 200 µg desmopressin

Tablets containing the following ingredients were prepared by the usual wet granulation method: Desmopressin (PoliPeptide Laboratories, Sweden)

Lactose (Pharmatose 150M, DMV, The Netherlands)

Potato starch (Lyckeby AB, Sweden)

PVP (Kollidon 25, BASF, Germany)

Magnesium stearate (Peter Greven, Germany)

Granulating liquid (water, ethanol) [removed during processing]

Comparative Example 3. Plain tablet with 100 µg of desmopressin

The procedure of Comparative Example 2 was followed, except that the amount of desmopressin was 100 µg / tablet.

Example 7 Bioavailability of desmopressin administered as the formulations of Examples 4-6 Test design

The trial was carried out on 24 healthy male non-smoking volunteers. The study was designed as a single-center, open-label, randomized, balanced four-way Phase I cross-over study. Each subject was administered desmopressin in random order as an orally dispersible 200 μg, 400 μg, and 800 μg dosage form (Examples 4, 5 and 6, respectively). ) and a dose of 2 µg as an intravenous bolus (Comparative Example 1). The washout period between doses was 72 hours. To normalize the oral mucosa prior to administration of the orodispersible tablet, subjects were asked to refrain from eating, chewing gum, etc. Subjects were allowed to brush their teeth in the morning prior to drug administration, but without toothpaste.

Blood samples

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

Test

Plasma desmopressin concentration was determined by a validated RIA method.

Apartakokinetic analysis

Plasma desmopressin concentrations were analyzed for individual volunteers in each administration group by the use of non-compartmental methods using the available WinNonlin ™ Pro, version 3.2 software (Pharsight Corporation, US). Plasma concentrations below the limit of quantification (LOQ) followed by values ​​above the LOQ are presented as - "LOQ / 2" for NCA analysis and for descriptive concentration statistics. Values ​​below LOQ. which were not followed by values ​​above the LOQ were excluded from the NCA analysis and assigned a value of zero in the descriptive concentration statistics.

Pharmacokinetic analysis results

Following intravenous administration, the mean volume of distribution at steady state (Vss) was 29.7 dm³. The mean calculated clearance was 8.5 dm³/ h and the assigned mean elimination half-life was

2.8 hours. After oral administration of desmopressin, peak plasma concentrations were observed 0.5-2.0 hours after dosing. Peak plasma concentrations were 14.25, 30.21 and 65.25 μg / ml, respectively, after the dose of 200. 400 and 800 μg. After reaching the maximum level, desmopressin was eliminated with a mean elimination half-life of 2.8-3.0 hours. The bioavailability was determined to be 0.30% with a 95% confidence interval of 0.23-0.38%.

The pharmacokinetics of desmopressin are linear when administered as the orally dispersible dosage form of Examples 4, 5 or 6.

COMPARATIVE EXAMPLE 4. Bioavailability of desmopressin administered as the formulations of Comparative Examples 2 and 3

PL 208 482 B1

Thirty-six healthy male (Caucasian, Black, and Hispanic) males participated in the trial, and the study was designed as an open-label, single-dose, three-way crossover study. Each subject was administered, in random order, 200 µg of desmopressin as a single tablet of a 200 µg tablet (Comparative Example 2). 200 µg of desmopressin as 2 tablets of 100 µg (comparative example 3) and a dose of 2 µg as an intravenous bolus (comparative example 1).

Following intravenous administration, the mean elimination half-life was 2.24 hours. After oral administration of desmopressin, peak plasma concentrations were observed at 1.06 hours (2 x 100 μg) or 1.05 hours (1 x 200 μg) after dosing. Peak plasma concentrations were 13.2 and 15.0 μg / ml, respectively, after an oral dose of 2 x 100 μg and 1 x 200 μg. The bioavailability was found to be 0.13% (2 x 100 pg) or 0.16% (1 x 200 pg).