RU2260424C9 - New composition for oral administration - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a solid pharmaceutical composition. The composition comprises tegaserod or its salts as an active component that is sensitive to acid effect and/or difficultly soluble in water, and a loosening agent taken in the amount at least 15 wt.-% as measured for the total mass of the composition. The composition is stable and can be prepared easily, it shows good rate release after its administration patients and good biological availability. The composition is designated for prophylaxis, modulation or treatment of visceral pain or discomfort, for modulation of visceral sensitivity or perception, improvement of sensory perception of rectum intestine tension and for treatment of anal dysfunction regulation.

EFFECT: improved and valuable medicinal properties of composition.

14 cl, 7 ex

Description

The present invention relates to a pharmaceutical composition, in particular to a composition intended for the administration of active substances that are slightly soluble in aqueous media and / or sensitive to the action of acids. More specifically, the present invention relates to a pharmaceutical composition for the administration of active substances that affect the gastrointestinal system. The present invention also relates to a method for preparing such compositions. The term "pharmaceutical" also includes use in the field of veterinary medicine.

The preparation of pharmaceutical compositions containing active substances that are slightly soluble in aqueous media and / or sensitive to the action of acids, is difficult. One of the problems that may occur is the adsorption of the active substance on the production equipment during the manufacturing process. Due to the poor solubility of such active ingredients, it is also difficult to obtain pharmaceutical compositions that have a good dissolution rate after administration. Another problem is that the active substances can decompose, for example, chemically, under acidic conditions during the manufacturing process or during storage of the composition.

The present invention provides compositions and methods for eliminating or minimizing one or more of the above difficulties.

When creating the invention, it was unexpectedly found that it is possible to prepare a pharmaceutical composition intended for the administration of active substances that are slightly soluble in aqueous media, for example pure water, and / or sensitive to the action of acids, which after administration has good solubility characteristics, good biological availability and unexpectedly high performance.

One of the objects of the present invention is a solid pharmaceutical composition for oral administration, for example, a tablet containing an active substance that is slightly soluble in aqueous media and / or sensitive to acids, and a disintegrant, for example a super disintegrant, present in an amount of at least 15 wt.% in terms of the total weight of the composition.

The term "slightly soluble" means that the active substance has at room temperature, for example at 25 ° C, solubility in aqueous media of more than 0.001% and less than 10%, for example less than 1%, for example less than 0.1%, for example less than 0.05 %, for example less than 0.02%.

The term "sensitive to the action of acids" means that the active substance, even under slightly acidic conditions, for example at pH 6, can be converted to a large extent into a decomposition product, for example, by chemical decomposition, which, for example, can lead within 2 hours, and may not lead to a change in activity. Examples of such compounds are known in the art and can be detected by standard experiments.

The term "disintegrant" means a substance or mixture of substances added to a solid pharmaceutical composition, such as a tablet, to facilitate disintegration or decomposition after administration, so that the active substance is released from the composition in the most efficient manner during its rapid dissolution (see, for example, " Remington's Pharmaceutical Science, 18th edition (1990), The Theory and Practice of Industrial Pharmacy, Lachmann et al., Lea and Febiger (1970)).

Applicants are aware of the difficulties in obtaining stable, commercially available compositions, for example tablets containing the compounds described in EP 505322 (incorporated herein by reference) and which can be used as agonists or partial agonists of the 5-HT ₄ receptor.

A preferred partial 5-HT ₄ receptor agonist described in EP 505322 is tegaserod (3- (5-methoxy-1H-indol-3-ylmethylene) -N-pentylcarbazimidamide) (see Example 13) of the formula

which in the present description is designated as compound A, or a pharmaceutically acceptable salt thereof, for example, acid maleate (hereinafter referred to as "kml"). Compound A has a solubility in water at 25 ° C. of about 0.02% and is sensitive to acids. Applicants have found that compositions that even in the stomach have good absorption can be prepared. It was also found that compound A can be adsorbed using certain excipients, so that its dissolution upon administration can be substantially reduced.

There are few publications on the biopharmaceutical characteristics of agonists, partial agonists or antagonists of the 5-HT ₄ receptor, in particular, their place of action is still unknown.

Another object of the present invention are pharmaceutical compositions that allow the complete dissolution of agonists, partial agonists or antagonists of the 5-HT ₄ receptor, in particular compound A, when administered to people, for example, patients in need thereof. These compositions have good bioavailability and unexpectedly high efficacy. In addition, they are stable and can be easily manufactured. A method for preparing them is also provided.

The active substances that can be used in the compositions of the present invention are, in a general sense, substances having activity against the gastrointestinal system, for example, serotonergic active substances, for example, complete agonists, partial agonists and antagonists of 5-HT ₄ receptors, wherein they are slightly soluble and / or sensitive to the action of acids. Preferably they are in salt form, for example, such as acid maleate or hydrochloride, they can also be in free form.

The 5-HT ₄ receptor is a cloned type of receptor from the serotonin family comprising at least 14 different G-protein-coupled receptors (with the exception of the ionophore receptor subtype of 5-HT ₃ ). Four splicing variants of the human receptor were identified, namely 5-HT _4A , 5-HT _4B , 5-HT _4C and 5-HT _4D , which differ in the length and sequence of the C-terminus of the protein (Blondel et al., FEBS Letters, 412: 465-474 (1997); Blondel et al., J. Neurochem. 70: 2252-2261 (1998)). Biochemical analysis of 5-HT ₄ receptors revealed a positive binding to adenylyl cyclase. It has been found that the expression of 5-HT ₄ receptor in humans occurs in the brain, intestines, atria, bladder and kidneys.

Compounds having activity against the serotonin receptor are substituted benzamides, for example cisapride, renzapride, zakoprid, kleboprid, cinitapride, mosapride: lintopride, metoclopramide or benzoic esters, for example RS 23597-190, SB 204070, SB 207710, or aminocuanidinides, prukaloprid, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532, tropizetron, alosetron, GR 113808, GR 125487, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3- (5-hydroxy-7-methyl-1H-indol-3-ylmethylene) -N-pentyl-N-methylcarbazimidamide, indazole-3-carbaxamides, 2-oxobenzamidazole-3-carboxamides (description nnye in EP 908 459, incorporated herein by reference).

5-HT ₄ receptor agonists are known as compounds that can activate 5-HT ₄ receptors at rest (full or partial activation). Examples of full agonists or partial agonists of a 5-HT ₄ receptor are (S) zakopride, cisapride, prucaloprid, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532 and the compound And, first of all, in the form of an acid maleate.

5-HT ₄ receptor antagonists are known as compounds that do not activate 5-HT ₄ receptors, but act as inhibitors of 5-HT ₄ receptor agonists. Examples of 5-HT ₄ receptor antagonists are GR 113808, GR 125487, SB 203186, SB 204070, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3- (5-hydroxy-7-methyl -1H-indol-3-ylmethylene) -N-pentyl-N-methylcarbazimidamide.

5-HT ₄ receptor agonists can be used to prevent and treat gastrointestinal motility disorders such as irritable bowel syndrome (IBS), reflux gastroesophagitis (GERD), functional dyspepsia (FD), and postoperative bowel obstruction (POI).

In a preferred embodiment, the composition according to the invention comprises from 20 to 60 wt.%, For example from 30 to 50 wt.%, For example 40 wt.% Disintegrant, calculated on the total weight of the composition. It was found that the use of such a large percentage of disintegrant increases the dissolution rate in an aqueous medium, and also prevents the adsorption of the active substance on excipients.

As disintegrants, the composition of the invention may include:

- crospovidone (with a molecular weight (MM)> 10 ⁶ ), e.g. Polyplasdon XL®, Kollidon CL®, Polyplasdon XL-10®,

- pre-gelled starch (MM: 30000-120000), for example starch 1500®, STA-Rx 1500®,

- sodium starch glycolate (MM: 500000-1000000), for example Primojel®,

- calcium carboxymethyl cellulose (SMS-Ca),

- sodium carboxymethyl cellulose (CMC-Na) (MM: 90000-700000), e.g. Ac-Di-Sol®,

- sodium alginate

or a mixture thereof.

Crospovidone, which is preferably insoluble in water, is preferably used as a disintegrant. Preferably, it has high capillarity or pronounced hydration ability and low gelling ability. Preferably, the particle sizes are about 1-500 microns. Preferably, the particle sizes are, for example, for Polyplasdon XL® less than 400 microns, for example for Polyplasdon XL-10® less than 80 microns, for example less than 74 microns, for example for Kollidon CL®, approximately 50% of the particles are larger than 50 microns and a maximum of 1% particles has a size of more than 250 microns. The preferred crospovidone is Polyplasdon XL-10®, for example, with a density of approximately 0.213 g / cm ³ (loose) or 0.273 g / cm ³ (dense).

The pharmaceutical composition of the invention may further include one or more excipients.

In addition, the composition may include one or more lubricants, for example, in an amount in the range of, for example, 1-20%, for example 5-15%, for example 10%, based on the weight of the composition.

Examples of such lubricants include

- a monoester of fatty acid and glycerol, for example, with a molecular weight of 200-800, for example glycerol monostearate (for example, Myvaplex®, with a purity corresponding to USP (US Pharmacopoeia)),

- polyethylene glycol (PEG) with a molecular weight of 100-10000, for example 1000-8000, for example 2000-6000, for example 2500-5000, for example Macrogol 4000 (powder) BP (British Pharmacopoeia),

- hydrogenated castor oil (e.g. Cutina®) and the like, or a mixture thereof.

In a preferred embodiment, the sizing is glycerol monostearate. The sizing properties of such a preferred composition can be improved by adding polyethylene glycol (PEG), for example Macrogol 4000 (powder) BP.

The composition according to the invention may include one or more surfactants, for example, in an amount in the range of 0.1-10%, for example 1-5%, for example, 2%, based on the total weight of the composition. Pharmaceutically acceptable surfactants may be nonionic or anionic.

As nonionic surfactants can be used:

polyoxyethylene sorbitan fatty acid esters (polysorbates; MM: 500-2000), for example mono- and trilauryl, -palmityl, -stearyl and -oleyl esters, for example Tween®, for example Tween 80®;

- polyoxyethylene fatty acid esters (MM: 500-5000), for example Myrij® or Cetiol®;

- copolymers of polyoxyethylene and polyoxypropylene, for example, with a molecular weight of 1000-20000, for example 6000-15000, for example 7000-10000, for example Pluronic® or Emkalyx®;

- block copolymers of polyoxyethylene and polyoxypropylene, for example, with a molecular weight of 1000-20000, for example 6000-15000, for example 7000-10000, for example Poloxamer 188®;

- reaction products of natural or hydrogenated castor oil and ethylene oxide, for example Cremophor®;

- dioctyl succinate or di [2-ethylhexyl] succinate;

esters of propylene glycol and a mono- or dibasic (for example, C ₆ -C ₈ ) fatty acid, for example Miglyol®;

or mixtures thereof.

As suitable anionic surfactants, for example, sodium lauryl sulfate or sodium docusate can be used.

Unless otherwise specified, a fatty acid or carbon-containing chain has from about 8 to 22 carbon atoms, for example C ₁₈ .

The composition of the present invention may contain one or more binders, for example, in an amount in the range of 1-10 wt.%, For example 2-8 wt.%, For example, comprising 5 wt.%. In particular, you can use:

- hydroxypropyl methylcellulose, for example, with a molecular weight of 10000-1500000, for example HPMC-3 (3mPa-s) (for example, Pharmacoat®, Methocel®),

- polyvinylpyrrolidone, for example, with a molecular weight of 2500-3000000, for example 8000-1000000, for example 10000-400000, for example 30000-50000 (for example, Kollidon®, Plasdon®),

- potato starch, wheat starch, corn starch, for example, with a molecular weight of 30000-120000, or a mixture thereof.

The composition of the invention may include one or more diluents, such as lactose, mannitol, sucrose, calcium sulfate, calcium phosphate, microcrystalline cellulose (Avicel®) in an amount in the range of, for example, 10-70%, for example 20-50%, for example, in an amount of 30% based on the weight of the composition. A preferred diluent is lactose, for example lactose with a particle size of 200 mesh (for example, DMV® or Alpavit®), for example, in the form of a monohydrate.

Other common excipients that may optionally be present in the composition include preservatives, stabilizers, release agents, or flow or slip enhancing agents based on silicon, for example silicon dioxide (e.g. Syloid®, Aerosil®), as well as FD & C dyes such as oxides gland.

Other excipients described in the literature may be used in the pharmaceutical compositions of the invention, for example, in the Fiedler Handbook, Lexicon der Hilfstoffe, 4th ed., ECV Aulendorf, 1996, and in the Handbook of Pharmaceutical Excipients, Wade and Weller (eds. Ry) (1994), the contents of which are incorporated into this description by reference.

The invention primarily relates to pharmaceutical compositions containing an active substance, for example an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example compound A, for example, its acid maleate, present in an amount that ranges from about 0.2% to about 20%, for example from 0.5% to 15%, and preferably from about 1% to about 10%, based on the weight of the composition.

A preferred composition of the invention may comprise from about 0.5 wt.% To about 15 wt.% The active substance, for example a 5-HT ₄ receptor agonist, for example compound A, for example acid maleate, from 20 to 60 wt.% Disintegrant, for example crospovidone, from 1 to about 20 wt.% a lubricant, for example glycerol monostearate, from 0.1 to about 10 wt.% a surfactant, for example poloxalcol, from about 10 to 50 wt.% diluent, for example lactose, and from 1 up to 10 wt.% a binder, such as hydra ksipropil-methylcellulose (e.g. HPMC-3). 1-10% by weight of PEG may also be added.

The mass ratio of the active substance and baking powder can be from 1: 1 to 1: 400, for example from 1: 5 to 1: 100, from 1: 8 to 1:50, for example, it can be from 1:16 to 1:20.

Another object of the invention is a pharmaceutical composition for oral administration, for example, a tablet comprising one of the above active ingredients, for example, a 5-HT ₄ receptor agonist, partial agonist or antagonist, for example tegaserod, the composition having the following solubility characteristics in water or in USP buffers at pH 6.8 and 7.4:

time (min) amount (in percent) 5 30-90 fifteen 80-100 thirty 95-100 60 one hundred

For example, a composition according to the invention, for example a composition containing tegaserod as an active substance, may have the following solubility characteristics in water or in USP buffers at pH 6.8 and 7.4:

time (min) amount (in percent) 5 48.9 fifteen 95.5 thirty 99.7 60 one hundred

Another object of the present invention is a composition intended for oral administration, for example, a tablet containing one of the above active ingredients, for example, an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example tegaserod, where after administration it is released within 5 minutes water or in USP buffers at pH 6.8 and 7.4 80% of the active substance.

The next object of the present invention is the use of a baking powder in an amount of at least 15 wt.% In the preparation of a pharmaceutical composition intended for the administration of an acid sensitive and / or slightly soluble active substance, for example, an active substance, for example a 5-HT ₄ receptor agonist , for example, compound A, for example, its acid maleate.

The pharmaceutical compositions of the present invention can be used in known indications for the administration of the specific active substance contained therein.

The exact amounts of the active substance and the composition to be administered depend on various factors, for example, the condition to be treated, the duration of treatment required and the rate of release of the active substance.

In particular, the required amount of active substance and the rate of release can be determined on the basis of generally accepted methods for determining in vitro and in vivo how long the concentration of a specific active substance in the blood plasma remains at a level acceptable to achieve a therapeutic effect.

The approximate doses included in a solid preparative form, for example, in a tablet, for the treatment of irritable bowel syndrome (IBS) are from 1 mg to 12 mg of active ingredient, for the treatment of functional dyspepsia (FD) and reflux gastroesophagitis (GERD) - from 0, 2 to 2 mg of the active substance, in particular compound A, for example its acid maleate, per day for a mammal weighing 70 kg, for example for humans, as well as for standard model animals. The increased tolerance of the active substance, in particular compound A, for example, its acid maleate, with the introduction of the compositions can be demonstrated using standard experiments using animals, as well as in clinical trials.

The pharmaceutical composition of the invention, comprising an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, can be used primarily to improve sensory perception of rectal stretching, for example, in the treatment of encopresis (fecal incontinence), or to prevent, modulate or treat visceral pain or discomfort.

It was found that agonists, partial agonists or antagonists of the 5-HT ₄ receptor, for example, as described in EP-A1 505322, due to their known activity, for example due to the stimulating effect against peristaltic reflex observed in experiments on the isolated ileum of the guinea pig , as described in EP-A1 505322, can be used to treat disorders of the motility of the gastrointestinal tract, for example, to normalize or improve the emptying of the stomach and intestinal patency in patients suffering from impaired staltiki such as irritable bowel syndrome.

When creating the present invention, it was unexpectedly found that agonists, partial agonists or antagonists of the 5-HT ₄ receptor can have a beneficial effect, for example, they can have modulating effects on the sensory perception of rectal stretching and on visceral sensitivity or perception.

It is known that the characteristics of receptors are not the same throughout the intestine and that the type of afferent innervation reflects the essence of the phenomena occurring in a particular organ. For example, the rectum refers to those parts of the gastrointestinal tract from which pain is not transmitted, in contrast, only painful sensations can come from the colon.

Encopresis may be due to functional disorders of the basic mechanisms of anal regulation. Anal regulation, apparently, is based on the coordinated functioning of the neuromuscular mechanism that controls the sensations and stretching of the rectum, inhibiting recto-anal reflex, reflex contractions of the external anal sphincter and pubic rectal muscle. Although contractions of the skeletal muscles (external sphincter and pubic-rectal muscle) are very important for maintaining regulation, the initiating effect of sensation and perception in the rectum, which plays a decisive role, is often often anomalous in patients with incontinence. Anal incontinence is a dysfunction that occurs primarily in diabetics and the elderly.

There is a need to develop medical means for modulating visceral sensitivity, discomfort or pain in patients suffering from gastrointestinal tract disorders, and for treating anal dysfunction dysfunctions.

Specific objects of the present invention are:

1.1. A method for preventing, modulating or treating visceral, for example abdominal, pain or discomfort in a patient in need thereof, comprising administering to the patient an effective amount of a 5-HT ₄ receptor agonist, partial agonist or antagonist or a pharmaceutically acceptable salt thereof.

1.2. A method for modulating visceral sensitivity or perception in a patient in need thereof, comprising administering to the patient an effective amount of a 5-HT ₄ receptor agonist, partial agonist or antagonist or a pharmaceutically acceptable salt thereof.

1.3. A method of stimulating 5-HT ₄ receptors present on afferent nerve endings, especially on external neurons in the intestine, in a patient in need thereof, comprising administering to the patient an effective amount of a 5-HT ₄ receptor agonist or partial agonist or a pharmaceutically acceptable salt thereof .

1.4. A method for modulating visceral sensitivity, discomfort or pain by stimulating 5-HT ₄ receptors present on afferent nerve endings, especially on external neurons in the intestine, in a patient in need thereof, comprising administering to the patient an effective amount of a 5- agonist or partial agonist HT ₄ receptor or a pharmaceutically acceptable salt thereof.

1.5. A method for regulating or stabilizing afferent nerve fibers of the muscular-intestinal plexus in a patient in need thereof, comprising administering to the patient an effective amount of a 5-HT ₄ receptor agonist or partial agonist or a pharmaceutically acceptable salt thereof.

1.6. A method for improving the sensory perception of rectal distension in a patient in need thereof, comprising administering to the patient an effective amount of a 5-HT ₄ receptor agonist, partial agonist or antagonist or a pharmaceutically acceptable salt thereof.

1.7. A method for treating anal regulation dysfunctions in a patient in need thereof, comprising administering to the patient an effective amount of a 5-HT ₄ receptor agonist, partial agonist or antagonist, or a pharmaceutically acceptable salt thereof.

In addition, objects of the present invention are also:

2. An agonist, partial agonist or antagonist of a 5-HT ₄ receptor or a pharmaceutically acceptable salt thereof, intended for use according to the method described above in items 1.1-1.7; or

3. An agonist, partial agonist or antagonist of a 5-HT ₄ receptor or a pharmaceutically acceptable salt thereof, intended for the preparation of a pharmaceutical composition used according to the method described above in claims 1.1-1.7; or

4. A pharmaceutical composition intended for use according to the method described in § 1.1-1.7, which contains a 5-HT ₄ receptor agonist, partial agonist or antagonist or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable diluents or carriers, for example a composition as described above.

Preferred compounds used according to the invention include, for example, the above compounds, especially full agonists or partial agonists of the 5-HT ₄ receptor, for example (S) zakopride, cisapride, prucaloprid, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532, especially compound a and particularly in the form of its acid maleate, more preferably selective agonists or partial agonists of the 5-HT ₄ receptor antagonists and 5-HT ₄ receptor, e.g. tropizetron, GR 113808, GR 125487, SB 204070, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3- (5-hydroxy-7-meth l-1H-indol-3-ylmethylene) -N-pentyl-N-metilkarbazimidamid etc. The term "selective" means that the compound practically does not bind or does not stimulate the 5-HT ₃ receptor of serotonin. The group of compounds does not include tropizetron.

The possibility of using an agonist, partial agonist or antagonist of a 5-HT ₄ receptor to prevent, modulate or treat visceral, such as abdominal pain or discomfort, or modulate visceral sensitivity or perception, or to regulate or stabilize the afferent nerve fibers of the muscular-intestinal plexus demonstrated using standard tests, for example, as described below.

Decerebrated non-anesthetized cats, under constant monitoring of blood pressure, are paralyzed by intravenous injection of (iv) Alcuronium chloride dissolved in reomacrodex (initial dose of 200 μg / kg, then additional doses of 100 μg / kg if necessary), and artificially ventilated. Using the unipolar method, the activity of individual afferent fibers from the peripheral ends of the sacral dorsal roots dissected in the center is recorded. Stretch receptors are identified by sensing their sensory regions in the wall of the mobilized rectum. After that, the response of individual fibers to barostat-controlled spasmodic rectal stretching is determined. The quantitative characteristics of the reaction of individual fibers are evaluated based on tensile pressure and the resulting rectal diameter. Alternatively, the response of individual fibers to pressure-induced peristalsis is measured.

After obtaining 2 stretch profiles (5 min each) and / or 10 min peristalsis under controlled conditions, an iv agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example compound A, or a carrier is administered and the protocol is repeated. Then, according to the stretching / peristalsis protocol, the activity of other individual fibers is measured in the presence of an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example, compound A or a carrier. In this experiment, the intensity of salvo of afferent fibers in the rectum decreased after administration of an agonist or partial agonist of a 5-HT ₄ receptor at a dose of 0.1 to 3 mg / kg iv at a tensile pressure exceeding 20 mm Hg. With the introduction of compound A iv in increasing doses from 0.15 to 1.2 mg / kg, the most significant inhibition was achieved at 60 mm Hg, and a decrease of half the maximum was achieved at a dose of approximately 0.7 mg / kg.

The possibility of using an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example Compound A, for the treatment of anal incontinence, as well as for the treatment of the above conditions can be demonstrated using the method described below.

In 10 healthy hungry volunteers, intracavitary pressures and reactions in the last section of the colon 60 cm long are measured using a perfusion pressure gauge. Volumetric stimulation is carried out using three latex balloons placed at a distance of 50, 30 and 10 cm. Initial values of intracavitary pressure in the colon and reflexes are determined. Then reflex inhibitory relaxation of the internal anal sphincter is initiated by filling the cylinders with gas in 10 ml portions until the maximum volume of 150 ml is reached. During the filling phase, two parameters are evaluated: a) a reflux threshold (a volume capable of inducing a significant decrease in pressure of the internal anal sphincter) and b) a reaction threshold (a volume capable of inducing a conscious defecation reflex). After registration of the basic parameters, p was administered to each patient. about. an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example Compound A, and after 30-90 min, intracavitary colon pressure and reflexes were again evaluated using the same method. In this experiment, an agonist, partial agonist or antagonist of a 5-HT ₄ receptor, for example compound A, significantly reduced the reaction threshold when administered at a dose of 2-12 mg p.o.

Agonists, partial agonists or antagonists of the 5-HT ₄ receptor, for example compound A, can be administered by any conventional route, in particular enteral, preferably oral, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, or suppository form.

Agonists, partial agonists or antagonists of the 5-HT ₄ receptor, for example compound A, can be administered either in free form or in the form of a pharmaceutically acceptable salt. The activity of such salts is of the same order as the activity of free-form 5-HT ₄ receptor agonists, partial agonists or antagonists.

The daily doses necessary for the practical implementation of the present invention may vary, for example, depending on the particular compound employed, the route of administration and the severity of the condition to be treated. The indicated daily dose for parenteral administration is in the range from about 0.05 to about 30 mg, for example from about 0.05 to about 5 mg, and for oral administration from about 0.1 to about 30 mg, it is convenient to administer it as a single doses either in divided doses 2-4 times a day, or in the form for continuous release. Dosage units for oral administration respectively contain from about 0.5 to about 30 mg of a 5-HT ₄ receptor agonist, partial agonist or antagonist, for example Compound A, or a pharmaceutically acceptable salt thereof, in admixture with an appropriate solid or liquid pharmaceutically acceptable diluent or carrier.

In addition, it was found that a 5-HT ₄ receptor agonist or partial agonist, for example Compound A, can preferably be used to prevent or treat gastrointestinal motility disorders, for example, they have a stimulating effect on the motility of the gastrointestinal tract in horses and cattle.

In accordance with these objects of the invention are also:

5.1. A method for preventing or treating gastrointestinal motility disorders, for example, by stimulating gastrointestinal motility in horses and cattle that need it, comprising administering to horses or cattle an effective amount of a 5-HT ₄ agonist or partial agonist - a receptor, for example compound A, or a pharmaceutically acceptable salt thereof.

5.2. A method for preventing or treating gastrointestinal motility disorders, for example, after colon surgery, for example postoperative ileus (bowel obstruction) in horses and cattle that need it, comprising administering to horses or cattle an effective amount of an agonist or a partial 5-HT ₄ receptor agonist, for example Compound A, or a pharmaceutically acceptable salt thereof.

6. An agonist or partial agonist of a 5-HT ₄ receptor, for example Compound A, or a pharmaceutically acceptable salt thereof, intended for use as a veterinary pharmaceutical agent, for example, for horses and cattle, for example, according to any of the above methods 5.1 or 5.2, or for the manufacture of a veterinary pharmaceutical product, for example, for use according to the method specified in clause 5.1 or clause 5.2.

7. A pharmaceutical composition for use in veterinary medicine, for example for the treatment of horses or cattle, for example, according to any of the above methods 5.1 or 5.2, containing a 5-HT ₄ receptor agonist or partial agonist, for example compound A, or a pharmaceutically acceptable thereof a salt in combination with a pharmaceutically acceptable diluent or carrier, for example a composition as described above.

Preferred 5-HT ₄ receptor agonists or partial agonists that can be used according to the invention for treating horses or cattle include the above compounds, for example (S) zakopride, prucaloprid, SB 205149, SC 53116, RS 67333, RS 67506 , BIMU 1, BIMU 8, (S) -RS 56532, especially Compound A, and especially in the form of its acid maleate, more preferably a selective 5-HT ₄ receptor agonist or partial agonist.

The applicability of a 5-HT ₄ receptor agonist or partial agonist, for example Compound A, for the treatment of postoperative ileus, as well as the applicability for treating the above conditions in horses or cattle can be demonstrated using the method described below.

Twenty horses with intestinal colic syndrome underwent abdominal surgery. During surgery, they underwent maintenance therapy. At the end of the surgery, they were given iv or im (intramuscularly) a specific 5-HT ₄ receptor agonist or partial agonist, for example Compound A, for example at a dose of 0.01 to 10 mg / kg. This dose was re-administered every 8-24 hours until spontaneous defecation was observed. Gastrointestinal motility was assessed, for example, by the presence or absence of gastric reflux, determined by nasogastric intubation, by the presence of rumbling in the digestive tract and by the time of defecation after the first injection of the test compound. In this experiment, test compounds, for example Compound A, were found to be effective in restoring normal intestinal peristaltic function in horses.

The daily doses necessary for the practical implementation of the method of the present invention in veterinary medicine may vary, for example, depending on the particular compound used, the route of administration and the severity of the condition to be treated. The indicated daily dose for parenteral administration is in the range from about 0.01 to about 10 mg / kg, for example from about 0.05 to about 5 mg / kg, it is convenient to administer it in a single dose or in divided doses 2-4 times per day, or in a continuous release form.

A further object of the present invention is a method for preventing or treating gastrointestinal motility disorders in a patient, for example, a human or animal in need of such therapy, comprising administering to the patient an effective amount of a composition of the present invention.

Another object of the invention is a method for improving the aqueous solubility of a pharmaceutical composition containing an acid-sensitive and / or slightly water-soluble active substance, for example a 5-HT ₄ receptor agonist, more particularly compound A, for example, in the form of an acidic maleate.

The pharmaceutical composition of the invention can be prepared by any conventional method known in the art, for example by mixing an appropriate amount of an active substance, for example a 5-HT ₄ receptor agonist, with at least 15 wt.%, For example 20-60 wt.%, for example 30-50 wt.%, for example with 40 wt.% baking powder, calculated on the total weight of the composition.

The composition is preferably prepared in solid form, for example, as a unit dose. Standard forms include capsules and preferably compressed forms, such as tablets.

The pharmaceutical composition according to the invention can be prepared, for example, using a wet process, for example using an aqueous base, granulation (technological equipment, for example, made of glass, can be pretreated with a siliconizing agent), comprising the following sequentially performed steps:

I) pre-mixing an acid-sensitive and / or slightly soluble in an aqueous medium active substance, for example a 5-HT ₄ receptor agonist, for example compound A, for example its acid maleate, with 60-98% diluent and subsequent sieving of the resulting mixture,

II) mixing purified water with a binder in a mass ratio of 1:20 to 3:20 and mixing until dissolved,

III) adding a surfactant to the solution obtained in stage II and mixing until dissolved,

IV) adding a baking powder, the remaining amount of diluent and 50-70% of the first sizing to the pre-mixture obtained in stage I, and mixing,

V) wetting with stirring the mixture obtained in stage IV, the granulation solution obtained in stage III,

VI) granulation with stirring of the mixture obtained in stage V,

VII) drying the granules to achieve the necessary moisture loss during drying, for example, to obtain a mixture for tabletting,

VIII) sorting granules by size by sieving.

In the manufacture of tablets, the granules obtained in stage VIII are mixed, for example, in a free-mixing mixer with the remainder of the first sizing and the second sizing to obtain the desired final tabletting mixture, which can be compressed into tablets. This can be done using conventional tabletting machines, for example using a rotary machine, at pressures of, for example, from 2 to 30 kN, for example from 5 to 27 kN, for example from 10 to 20 kN (kN stands for kilonewton).

The composition according to the invention can also be made using an alternative wet granulation process, according to which the preliminary mixing and sieving specified for stage I is not carried out. In this case, the active substance, baking powder, diluent and approximately 60% of the first sizing agent are pre-mixed and then moistened with a moisturizing the solution obtained in stage IV.

Compositions containing any of the aforementioned active substances may be prepared by the method described above.

If necessary, the pharmaceutical compositions of the invention are stored under conditions of low relative humidity, for example at 0V (relative humidity) below 50%, for example below 30-50%, at room temperature, preferably below 20 ° C. Compositions are storage stable systems. Only slight decomposition was found after storage for up to 1 year at room temperature, for example, at 25 ° C.

The compositions of the invention may be packaged in a standard manner to protect against moisture, for example in a blister pack, optionally together with a desiccant.

The compositions of the invention may have a water content of from 0 to 3% by weight, based on the total weight of the composition.

Another object of the present invention is a composition, in particular containing compound A, prepared by any of the methods described above, which allows to obtain a stable form of a small size.

Examples

The following examples illustrate the manufacture on an industrial scale of compositions containing compound A (kml) using the wet granulation process described above.

Example 1

Compositions in the form of tablets weighing 2 mg can be obtained according to the method described below.

a) Obtaining a granular product

Pre-Mixing Stage

1. 4.432 kg of compound A (kml) and 28.688 kg of lactose monohydrate are mixed in a high-speed mixer (type Colette Gral® 300 I or Fielder®); mixer speed controller position: 1; position of the knife speed controller: 1); for about 1.5 minutes, or in a mixer with free mixing (type Turbula®, Soneco® or

2. Then the pre-mixture obtained in stage 1 is sieved (granulator with a vibrator, for example of the type Frewitt® or Erweka®; mesh size: 0.8 mm).

3. The total amount of the preliminary mixture is divided into two portions of 16.560 kg each.

Obtaining a solution for granulation

4. Weigh approximately 40 kg of purified water.

5. To the purified water prepared in stage 4, add 3,600 kg of methylhydroxypropyl cellulose 3 maps and the mixture is stirred until dissolved.

6. To the solution obtained in step 5, 1.440 kg of poloxamer 188 are added and mixed until dissolved.

Granulation stage

7. Weigh 28.800 kg of crospovidone, 10.080 kg of lactose monohydrate and 4.320 kg of glycerol monostearate.

8. One portion of the pre-mixture obtained in stage 3 is added to the excipients prepared in stage 7, and the resulting product is mixed in a forced-mixer, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of mixer speed controller: 1 ; position of the knife speed controller: 1) for approximately 2 minutes

9. The mixture obtained in stage 8 is moistened with the granulation solution obtained in stage 6 with stirring in a mixer with forced mixing, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of the mixer speed controller: 1; position of the speed controller knife: 0; pumping speed of approximately 4 kg / min) for approximately 12 minutes

10. Weigh approximately 2 kg of purified water.

11. The vessel used in stage 6 is washed with purified water prepared in stage 10, and the product is added with stirring to the mixture obtained in stage 9.

12. The resulting mass is granulated with stirring in a mixer with forced mixing, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of the mixer speed controller: 1; position of the knife speed controller: 1) for about 2.5 minutes

Drying stage

13. The granules obtained in step 12 are dried in a fluidized bed air dryer (for example, Glatt® or Aeromatic®) for approximately 65 minutes (inlet air temperature of approximately 70 ° C) until drying moisture loss (PPP) is achieved, required for the tabletting mixture, i.e. up to PPP ≤4.4%.

14. Granules are sorted by sieving (pore size 0.8 mm) using a granulator with a vibrating sieve, for example, Frewitt® or Erweka® type).

15. Repeat steps 4-14 using a second crop of the product obtained in step 3.

b) Obtaining a mixture for tabletting

16. Sifted 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glycerol monostearate (granulator with a vibrator, for example, such as Frewitt® or Erweka®; mesh size: 0.8 mm).

в течение приблизительно 20 мин (10 об/мин), получая требуемую конечную смесь для таблетирования.17. The ingredients obtained in stage 16 are added to the total weight of the granular product and mixed in a mixer with free mixing, for example, type Soneco® or

for approximately 20 min (10 rpm), obtaining the desired final mixture for tabletting.

c) Stage of pressing

18. The tabletting mixture obtained in step 17 is compressed into tablets using compression pressures of 11, 14, or 17 kN on a rotary tabletting machine, for example of the type Fette®, Korsh®, Kelian® or Coarty® (temperature <20 ° С; ОВ (relative humidity) <40%).

Example 2: The composition of the composition for tablets weighing 2 mg (1 mg of the base corresponds to 1.385 mg of acid maleate compound A)

Compound A (kml) 2.77 (2 mg, calculated on the basis) Polyplasdone XL USP / NF 36.00 USP / NF Glycerol Monostearate 9.00 poloxalcol 1.80 lactose 200 mesh 30.53 HPMC (hydroxypropyl methylcellulose) 3cPs 4,50 polyethylene glycol 400 5.40 adsorbed water 2.00 Total 92 mg

Example 3

A composition in the form of a tablet weighing 6 mg can be prepared according to the process described below.

a) Obtaining a granular product

Obtaining a solution for granulation

1. Weigh approximately 40 kg of purified water.

2. To the purified water prepared in stage 1, 3,600 kg of 3 maps methylhydroxypropyl cellulose are added and mixed until dissolved.

3. To the solution obtained in stage 2, add 1,440 kg of poloxamer 188 and mix until dissolved (with stirring in a mixer).

Granulation stage

4. Weigh 4.787 kg of Compound A (kml) and 28.800 kg of crospovidone, 21.853 kg of lactose monohydrate and 4.320 kg of glycerol monostearate.

5. The ingredients prepared in step 4 are mixed in a forced-mixer, for example a Colette Gral® 300 I or Fielder® type mixer (position of mixer speed controller: 1; position of knife speed controller: 0) for approximately 2 minutes.

6. The mixture obtained in stage 5 is moistened with the granulation solution obtained in stage 3 by mixing in a mixer with forced mixing, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of the speed controller of the mixer: 1; position of the speed controller knife: 0; pumping speed of approximately 4 kg / min) for approximately 12 minutes

7. Weigh approximately 2 kg of purified water.

8. The vessel used in stage 3 is washed with purified water prepared in stage 7, and the product is added with stirring to the mixture obtained in stage 6.

9. The resulting mass is granulated with stirring in a mixer with forced mixing, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of the mixer speed controller: 1; position of the knife speed controller: 1) for about 2.5 minutes.

Drying stage

10. The granules obtained in step 9 are dried in a fluidized bed air dryer (for example, Glatt® or Aeromatic®) for approximately 65 minutes (inlet air temperature of approximately 70 ° C) until drying moisture loss (PPP) is achieved, required for the tabletting mixture, i.e. up to PPP ≤4.4%.

11. The granules are sized by sieving (pore size 0.8 mm) using a granulator with a vibrating sieve, for example of the type Frewitt® or Erweka®.

12. Repeat steps 1-11.

b) Obtaining a mixture for tabletting

13. Sift 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glycerol monostearate (granulator with a vibrator, for example, such as Frewitt® or Erweka®; mesh size: 0.8 mm).

в течение приблизительно 20 мин (10 об/мин), получая требуемую конечную смесь для таблетирования.14. The ingredients obtained in step 13 are added to the total weight of the granular product and mixed in a free-fall mixer, for example of the type Soneco® or

for approximately 20 min (10 rpm), obtaining the desired final mixture for tabletting.

c) Stage of pressing

15. The tabletting mixture obtained in step 14 is compressed into tablets using compression pressures of 13, 16 or 19 kN on a rotary tabletting machine such as Fette®, Korsh®, Kelian® or Coarty® (temperature <20 ° C; 0V (relative humidity) <40%).

Example 4: The composition of the composition for tablets weighing 6 mg (1 mg of the base corresponds to 1.385 mg of acid maleate compound A)

Compound A (kml) 8.31 (6 mg in terms of base) Polyplasdone XL USP / NF 50.00 USP / NF Glycerol Monostearate 12.50 poloxalcol 2,50 lactose 200 mesh 37.94 HPMC (hydroxypropyl methylcellulose) 3cPs 6.25

Compound A (kml) 8.31 (6 mg in terms of base) polyethylene glycol 400 7.50 adsorbed water 3.00 Total 128 mg

Example 5

A composition in the form of a tablet weighing 0.5 mg can be prepared according to the process described below.

a) Obtaining a granular product

Pre-Mixing Stage

1. 1.994 kg of Compound A (kml) and 31.126 kg of lactose monohydrate are mixed in a forced-mixer type Colette Gral® 300 I or Fielder®; mixer speed controller position: 1; position of the knife speed controller: 1) for approximately 1.5 minutes, or in a mixer with a free mixing type Turbula®, Soneco® or

2. Then the pre-mixture obtained in stage 1 is sieved (granulator with a vibrator, for example of the type Frewitt® or Erweka®; mesh size: 0.8 mm).

3. The total amount of the preliminary mixture is divided into two portions of 16.560 kg each.

Obtaining a solution for granulation

4. Weigh approximately 43 kg of purified water.

5. To the purified water prepared in stage 4, add 3,600 kg of methylhydroxypropyl cellulose 3 maps and the mixture is stirred until dissolved.

6. To the solution obtained in step 5, 1.440 kg of poloxamer 188 are added and mixed until dissolved.

Granulation stage

7. Weigh 28.800 kg of crospovidone, 10.080 kg of lactose monohydrate and 4.320 kg of glycerol monostearate.

8. One portion of the pre-mixture obtained in stage 3 is added to the excipients prepared in stage 7, and the resulting product is mixed in a forced-mixer, for example in a Colette Gral® 300 I or Fielder®-type mixer (position of the mixer speed controller: 1 ; position of the knife speed controller: 1) for approximately 2 minutes

9. The mixture obtained in stage 8 is moistened with the granulation solution obtained in stage 6 with stirring in a mixer with forced mixing, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of the mixer speed controller: 1; position of the speed controller knife: 0; pumping speed of approximately 4 kg / min) for approximately 12 minutes

10. Weigh approximately 2 kg of purified water.

11. The vessel used in stage 6 is washed with purified water prepared in stage 10, and the product is added with stirring to the mixture obtained in stage 9.

12. The resulting mass is granulated with stirring in a mixer with forced mixing, for example in a mixer such as Colette Gral® 300 I or Fielder® (position of the mixer speed controller: 1; position of the knife speed controller: 1) for about 2.5 minutes

Drying stage

13. The granules obtained in stage 12 are dried in a fluidized bed air dryer (for example, Glatt® or Aeromatic®) for approximately 60 minutes (inlet air temperature of approximately 70 ° C) until drying moisture loss (PPP) is achieved, required for the tabletting mixture, i.e. up to PPP ≤4.5%.

14. Granules are sorted by sieving (pore size 0.8 mm) using a granulator with a vibrating sieve, for example, a Frewitt® or Erweka® type.

15. Repeat steps 4-14 using a second crop of the product obtained in step 3.

b) Obtaining a mixture for tabletting

16. Sifted 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glycerol monostearate (granulator with a vibrator, for example, such as Frewitt® or Erweka®; mesh size: 0.8 mm).

в течение приблизительно 20 мин (10 об/мин), получая требуемую конечную смесь для таблетирования.17. The ingredients obtained in stage 16 are added to the total weight of the granular product and mixed in a mixer with free mixing, for example, type Soneco® or

for approximately 20 min (10 rpm), obtaining the desired final mixture for tabletting.

c) Stage of pressing

18. The tabletting mixture obtained in step 17 is compressed into tablets on a rotary tabletting machine, for example of the type Fette®, Korsh®, Kelian® or Coarty® (temperature <20 ° C; RH (relative humidity) <40%).

Example 6: The composition of the composition for tablets weighing 0.5 mg (1 mg of the base corresponds to 1.385 mg of acid maleate compound A)

Compound A (kml) 0.6925 (0.5 mg in terms of base) Polyplasdone XL USP / NF 20.00 USP / NF Glycerol Monostearate 5.00 poloxalcol 1.00 lactose 200 mesh 17.8075 HPMC (hydroxypropyl methylcellulose) 3cPs 2,50 polyethylene glycol 400 3.00 adsorbed water 1.00 Total 51 mg

Example 7: The composition of the composition for tablets weighing 12 mg (1 mg of base corresponds to 1.385 mg of acid maleate compound A)

The manufacturing process is similar to the process used to make 6 mg tablets.

Compound A (kml) 16.62 (12 mg, calculated on the basis) Polyplasdone XL USP / NF 72.00 USP / NF Glycerol Monostearate 18.00 poloxalcol 3.60 lactose 200 mesh 49.98 Compound A (kml) 16.62 (12 mg, calculated on the basis) HPMC (hydroxypropyl methylcellulose) 3cPs 9.0 polyethylene glycol 400 10.8 adsorbed water 4.00 Total 184 mg

Claims (18)

1. A solid pharmaceutical composition for oral administration intended to prevent, modulate or treat visceral pain or discomfort, modulate visceral sensitivity or perception, improve sensory perception of rectal distension, and treat anal regulation dysfunction, containing compound A of the formula

or its salts and baking powder, which is present in an amount of at least 15 wt.% based on the total weight of the composition. 2. The composition according to claim 1, containing a baking powder, which is present in an amount of at least 15 wt.% Based on the total weight of the composition, and in which said baking powder is selected from the group consisting of crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, sodium alginate and their mixture. 3. The composition according to claim 1 or 2, in which compound A is in the form of an acid maleate salt (kml). 4. The composition according to any one of the preceding paragraphs, characterized in that the baking powder is present in an amount of from 20 to 60 wt.% Based on the total weight of the composition. 5. The composition according to any one of claims 1 to 3, characterized in that the baking powder is present in an amount of 40 wt.% Based on the total weight of the composition. 6. The composition according to any one of the preceding paragraphs, characterized in that the baking powder is crospovidone. 7. The composition according to any one of the preceding paragraphs, containing a sizing. 8. The composition according to claim 7, where the sizing is a monoester of fatty acid and glycerol. 9. The composition according to any one of the preceding paragraphs, where the sizing comprises a mixture of glycerol monostearate and polyethylene glycol. 10. The composition according to any one of the preceding paragraphs, containing a surfactant. 11. The composition of claim 10, where the surfactant is a poloxamer. 12. The composition according to claim 11, having the following solubility characteristics in water or artificial gastric juice: time (min) amount (in percent) 5 30-70 fifteen 80-100 thirty 95-100 60 one hundred 13. A composition according to any one of the preceding paragraphs, intended for the preparation of a medicament for preventing, modulating or treating visceral pain or discomfort, modulating visceral sensitivity or perception, improving sensory perception of rectal distension and treating anal regulation dysfunction in a subject in need thereof. 14. A method for preventing, modulating or treating visceral pain or discomfort to modulate visceral sensitivity or perception, improve sensory perception of rectal distension, or treat anal regulation dysfunction in a patient in need thereof, comprising administering to the patient an effective amount of a composition according to claims 1-12 . Priority on points: 08.21.1998 pp. 1-14; 10/27/1998 claims 1-14; 05/05/1999 pp. 1-14; 05/12/1999 pp. 1-14.