JP4808392B2 - Pharmacological composition concealing bitterness - Google Patents

Description

  The present invention relates to a formulation, in particular a powder, comprising a water-soluble bitter drug absorbed in a porous absorbent and a coating to mask the flavor, wherein the coating is a pharmaceutically acceptable surfactant. And a bitter-masking agent, wherein the bitter-masking agent is selected from pharmaceutically acceptable oils, fats, waxes, fatty alcohols or fatty acids. These disclosed formulations can mask the bitter taste of pharmacologically active compounds with a very strong bitter flavor, in particular epinastine, quinine or acetaminophen. These formulations are suitable for the preparation of numerous pharmaceutical dosage forms, preferably dry syrups.

If the pharmaceutical composition has a bitter flavor, these can be mixed with a sweetener to mask the bitter taste. However, often the sweeteners are not effective enough to mask the bitter taste of very bitter substances such as epinastine, quinine-hydrochloride or sulfate, or acetaminophen.
Epinastine and its acid addition salts, known chemically as 3-amino-9,13b-dihydro-1H-dibenz- [c, f] -imidazole- [1,5-a] -azepine, are based on EP 0,035,749 For the first time in German patent application P 30 08 944.2.
Chemically, epinastine is an amino base and does not reflect stereochemical features and is represented by the following formula:

Epinastine in particular has been used to treat allergies, pain, especially chronic pain and pain caused by inflammation, migraine, asthma, rhinitis, conjunctivitis and / or bronchitis (EP-B-0,035,749; EP 1000263) . In particular, epinastine is used for the treatment of allergy, dermatitis, rhinitis, conjunctivitis, bronchitis, asthma of skin diseases.
Epinastine is marketed in Japan under the brand name “Alesion ^™ ” and is most often used for its anti-histamine action.
Another interesting pharmacologically active substance is quinine. Quinine is a quinoline-alkaloid and is therefore also an amino base. Quinine has been used for the treatment of malaria, both now and even now, which has antipyretic, analgesic and muscle relaxant properties and can also be used as a labor pain inducer. It is well known that quinine has a bitter flavor and is therefore also used as an additive for certain soft drinks.

Due to its bitterness characteristics, it is also used as a reference substance for evaluating the bitterness of drugs.
Many attempts have been made in connection with concealing bitterness. For example, US Pat. No. 4,797,288 describes an edible material having a melting point of 100 ° C. or less, selected from a hydrophobic matrix of emulsifiers, fatty acids, natural waxes, synthetic waxes, and mixtures thereof that can be chewed or swallowed A drug release system is disclosed. This matrix is covered by a coating consisting of a combination of fatty acids and waxes. The degree of coating is 200-400% by weight, which leads to a decrease in its medicinal properties. Due to the high coating rate used and the materials used in the matrix, its drug release rate is expected to be delayed.

PCT-Patent Application WO 02/45693 describes a formulation that masks the bitter taste, which is one or more excipients selected from the group consisting of triglycerides, fatty alcohols, partial glycerides and fatty acid esters. Consists of active ingredients uniformly dispersed in an excipient matrix.
EP 455,391 discloses granules of a polyglycerol ester and a pharmacologically active substance produced in a fluidized bed. The fluidized bed is heated and the material is mixed in the heated fluidized bed until the polyglycerol ester melts and the particles agglomerate.

US Pat. No. 5,399,357 discloses a formulation comprising a fatty acid ester of polyglycerol and a microcrystalline wax. The dissolution rate of this drug is delayed, resulting in long-term release that is inappropriate for rapid drug action in the body. The system claimed here is a matrix, not a coating.
US Pat. No. 6,485,742 discloses a finely divided particulate formulation, which is a core made of a hydrophilic material covered with at least one coating layer made of a hydrophobic hot melt-lipid. Consists of substances.
Although these disclosures provide flavor concealed compounds, they typically use complex manufacturing processes and / or specially designed equipment for coating. Thus, the industrialization of such attempts results in expensive products. Thus, there is a need for formulations that are useful for masking the bitter taste of drugs with extremely bitter flavors and that are easy to industrially produce.

Surprisingly, a mixture of a pharmaceutically acceptable surfactant and a bitter-masking agent (or masking agent) selected from the group consisting of pharmaceutically acceptable oils, fats, waxes, fatty alcohols or fatty acids. Have found that they can mask the bitter taste of water-soluble pharmacologically active compounds with extremely bitter flavor, such as epinastine, quinine or its hydrochloride or sulfate, or acetaminophen.
The object of the present invention is therefore to provide a formulation, in particular a powder, comprising particles comprising a pharmacologically active compound with a water-soluble bitter flavor and a flavor-masking coating absorbed in the porous absorbent. In particular, in the formulation, the coating comprises a mixture of a pharmaceutically acceptable surfactant and a bitter-masking agent, the bitter-masking agent comprising a pharmaceutically acceptable oil, fat, wax, fat Selected from the group consisting of alcohols or fatty acids.

In one aspect, the present invention provides a formulation as follows:
a) a water-soluble pharmacologically active compound, preferably epinastine, quinine-hydrochloride or sulphate, or acetaminophen absorbed in a porous absorbent
b) containing a coating mixture covering the drug-carrying porous absorbent, wherein the coating comprises a mixture of at least one pharmaceutically acceptable surfactant and at least one bitter-masking agent. A formulation wherein the bitter-masking agent is selected from the group consisting of pharmaceutically acceptable oils, fats, waxes, fatty alcohols or fatty acids or mixtures thereof.

In a second aspect, the present invention provides a method for preparing a formulation, the method comprising the following steps:
a) dissolving the water-soluble pharmacologically active compound, preferably epinastine, quinine-hydrochloride or sulfate, or acetaminophen in a solvent;
b) a step of immersing a porous absorbent in the solution obtained in the step a) to allow the absorbent to absorb the pharmacologically active compound;
c) removing the solvent;
d) mixing at least one bitter-masking agent with at least one pharmaceutically acceptable surfactant; and
e) adding the coating mixture of step d) to the particles obtained in step c).
In a third aspect, the present invention provides a pharmacological formulation such as a tablet or dry syrup containing the above preparation.

One very desirable advantage of the preparations according to the invention is that even pharmacologically active compounds with a very high bitter taste such as epinastine or quinine can be masked by these formulations.
A bitter-masking coating prevents contact between the pharmacologically active compound and water and postpones elution of the pharmacologically active compound, and the bitter-masking agent acts on the taste receptor on the tongue. , Presumed to interfere with the stimulation of the original substance. According to this hypothesis, the bitter taste of many water-soluble components can be suppressed by using this technique. Furthermore, in connection with the process for producing the flavor-masking agent according to the invention, this process is very simple and the equipment required is very common. Compared to methods known in the art, it is very easy to produce industrially.

Within the scope of the present invention, the term “preparation” means particles composed of a drug-carrying porous absorbent covered with a flavor masking coating, the flavor masking coating being Contains a mixture of at least one surfactant and at least one bitter-masking agent.
Within the scope of the present invention, the term “epinastine” refers to 3-amino-9 as neutralized as the free base or as a pharmaceutically acceptable salt thereof, first described in German patent application P 30 08 944.2. , 13b-Dihydro-1H-dibenz- [c, f] -imidazole- [1,5-a] -azepine, the salt of which is hydrochloride, hydrobromide, oxalate, nitrate, sulfonate , Fumarate, maleate, sulfate, and phosphate.
The production method is described in EP 0496306 or WO 01/40229.
The terms “quinine” and “acetaminophen” refer to these drugs as neutralized or pharmaceutically acceptable salts thereof.

In connection with the first aspect, the present invention provides a formulation comprising:
In one aspect, the following formulation is provided:
a) a water-soluble pharmacologically active compound, preferably epinastine, quinine-hydrochloride or sulphate, or acetaminophen absorbed in a porous absorbent
b) containing a coating mixture over the porous absorbent carrying the drug, the coating comprising a mixture of at least one pharmaceutically acceptable surfactant and at least one bitter-masking agent. A formulation wherein the bitter-masking agent is selected from the group consisting of pharmaceutically acceptable oils, fats, waxes, fatty alcohols or fatty acids or mixtures thereof.

In connection with the porous absorbent that absorbs the pharmacologically active compound, in principle, any pharmaceutically acceptable absorbent capable of absorbing the drug can be used. Examples of suitable absorbents are magnesium aluminometasilicate, anhydrous silicic acid, calcium carbonate, hydrated silicon dioxide, magnesium silicate, medical carbon, silica gel, microcrystalline cellulose, starch, aluminum hydroxide gel, aluminum hydroxychloride , Magnesium aluminosilicate, sodium carboxymethyl starch or mixtures thereof. The use of magnesium aluminometasilicate is preferred.
In connection with the bitter-masking agent selected from the group consisting of pharmaceutically acceptable oils, fats, waxes, fatty alcohols or fatty acids or mixtures thereof suitable for coatings that mask the bitter taste, for example linseed oil , Kiri oil, soybean oil, peanut oil, sesame oil, palm oil, milk fat, rapeseed oil, corn oil, carnauba wax, cottonseed oil, esterified corn oil, orange oil, almond oil, safflower oil fatty acid, tocopherol acetate, chamomile oil, hydrogenated Soybean oil, stearic acid, safflower oil, hard fat, camellia oil, nuka oil, castor oil, coconut oil, olive oil, petroleum jelly, octyldecyl triglyceride, cocoa butter, medium chain fatty acid triglyceride, squalane, oleic acid, clove oil, white beeswax , Malt oil, stearyl alcohol or a mixture of these Compound can be used. The use of medium chain fatty acid triglycerides is preferred.

  In connection with the pharmaceutically acceptable surfactant suitable in combination with the bitter-masking agent, any low HLB (hydrophilic-hydrophobic balance) surfactant, such as an alkylallyl polyether alcohol, Fatty acid sucrose ester, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, fatty acid propylene glycol ester, lauryl sulfate, stearate, fatty acid sorbitan ester, fatty acid polyethylene glycol ester, fatty acid polyoxyethylene glycerol Esters, glycerol esters of fatty acids, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitol esters of fatty acids, polyoxyethylene alkyl allyl ethers, alkyl allyl sulfonates, coconut fat Acid diethanolamide, or polyoxyethylene sorbitan esters of fatty acids, or mixtures thereof can be used. The use of sucrose esters of fatty acids is preferred.

In this formulation, the amount of epinastine or salt thereof is in the range of 0.1-20% by weight, preferably in the range of 0.5-10% by weight, more preferably in the range of 2-5% by weight, and most preferably 2.5% by weight or 5%. It is in the range of mass%.
In a preferred formulation comprising quinine or acetaminophen, the amount of the pharmacologically active compound is in the range of 1-30% by weight and more preferably in the range of 5-10% by weight.
Prepare formulations with various contents of the coating mixture (mixture of the bitter-masking agent and the surfactant) to determine the appropriate amount of the coating mixture sufficient to mask the bitter taste The flavor was tested (see Example 4). The result indicates that the ratio of the coating mixture to the drug-carrying absorbent should be in the range of 0.5 to 1.2, preferably in the range of 0.7 to 1.2 or 0.8 to 1.2. If more of the coating mixture is used to increase this ratio and cover the particles, there is a risk that the resulting formulation will become a slurry. On the other hand, if the amount of the coating mixture is reduced, there is a risk that the bitter taste will not be sufficiently masked. However, the optimal ratio of the amount of the coating mixture to the amount of drug-carrying particles depends on the pharmacologically active compound used, and the absorption capacity of the absorbent and the coating agent used is routine. Can be determined by one of ordinary skill in the art.

  In order to determine the appropriate amount of the surfactant in the coating mixture, formulations with various surfactant contents were prepared and tested for their flavor (see Example 5). These results indicate that the amount of the surfactant should be 3% by weight or more and 50% by weight or less of the coating mixture. The amount of this surfactant is preferably in the range of 5-20%, more preferably 10-20%, most preferably 9-10% or 10-11% by weight of the coating mixture. However, the optimal ratio of the amount of surfactant in the coating mixture depends on the bitter-masking agent, the pharmacologically active compound and of course the surfactant used, and is determined by routine experimentation. Can be determined by the vendor.

  According to the present invention, the formulation preferably has a ratio of the coating mixture to the drug-carrying absorbent in the range of 0.5 to 1.2. Preferably, in such a formulation, the ratio of the coating mixture to the drug-carrying absorbent is in the range of 0.7 to 1.2 or 0.8 to 1.2, and the surfactant content in the coating mixture is 3 It is at least mass%. More preferably, in such a formulation, the ratio of the coating mixture to the drug-carrying absorbent is in the range of 0.7 to 1.2 or 0.8 to 1.2, and the content of the surfactant in the coating mixture is It exists in the range of 5-20 mass% or 10-20 mass%. Particularly preferred is a ratio of the coating mixture to the drug-carrying absorbent in the range of 0.7 to 0.9 or 0.9, and the surfactant content in the coating mixture is 9 to 10% by weight or 10%. It is a preparation in a range of ˜11% by mass. Particularly preferred is a ratio of the coating mixture to the drug-carrying absorbent in the range of 0.7 to 0.9, and a content of the surfactant in the coating mixture in the range of 9 to 10% by mass. It is a certain formulation.

In a second aspect, the present invention provides a method for preparing a formulation, the method comprising the following steps:
a) dissolving the water-soluble pharmacologically active compound, preferably epinastine, quinine-hydrochloride or sulfate, or acetaminophen in a solvent;
b) a step of immersing a porous absorbent in the solution obtained in the step a) to allow the absorbent to absorb the pharmacologically active compound;
c) removing the solvent;
d) mixing at least one bitter-masking agent with at least one pharmaceutically acceptable surfactant; and
e) adding the coating mixture of step d) to the particles obtained in step c).

  The preparation of the present invention is preferably produced through the following steps. The pharmacologically active compound is dissolved in a suitable solvent (for example, ethanol for epinastine hydrochloride). In principle, any solvent that does not destroy the porous absorbent particles can be used. Suitable solvents include but are not limited to water, acetone, ethanol, methanol, isopropanol and combinations thereof. As a next step, the porous absorbent particles are incubated with this solution (e.g., mixed in a blender and sprayed in a granulator) to bring the active ingredient into the porous absorbent (e.g., magnesium aluminosilicate). ). After the porous absorbent particles are incubated with the solution / suspension of the pharmacologically active compound, the drug-carrying particles need to be dried. The drug-carrying particles can be dried according to conventional methods known to those skilled in the art. For example, the drying can be performed by any suitable method such as freeze drying, tray drying, convection drying, microwave drying, contact drying, drying by infrared radiation, fluidized bed drying, and the like. Parameters such as drying time, drying temperature and number of drying cycles need to be adapted to the solvent used and the pharmacologically active compound, acceptable residual moisture, etc. Details of this method are known to those skilled in the art and are described, for example, in Pharmazeutische Technologie, Chapter 13, p.414-443 (Springer-Verlag, Berlin, Heidelberg, NY, 1998).

The thus prepared and dried drug-carrying absorbent particles are added to the powder of the dried drug-carrying absorbent particles and a mixture of the bitter-masking agent and a pharmaceutically acceptable surfactant is added. By mixing with the above, it is covered with the flavor masking layer. If the bitter-masking agent is a liquid at room temperature, a planetary mixer or a high shear mixer can be used without temperature control. If the content of the coating mixture is not very high, ordinary blenders such as V-shaped, W-cone or drum-shaped are also suitable. If the bitter-masking agent is a solid at room temperature, it must be melted before the coating step and the particles need to be cooled after the coating.
After this stage, the coated particles can be granulated with other ingredients, typically in a conventional manner.

The drug-carrying and coated drug product of the present invention is formulated to be an oral dosage form, i.e., the drug product, together with various pharmaceutically acceptable inert carriers, tablets, pellets Sachets, capsules, lozenges, troches, hard candy, powders, sprays, aqueous suspensions, elixirs, syrups, dry syrups and the like. Here, preferred dosage forms are dry syrups, sachets, powders and capsules. Particularly preferably, it is given as a dry syrup.
Such suitable carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Furthermore, such oral drug formulations can be suitably sweetened and flavored with various reagents of the type normally used for sweetening and flavoring purposes. In general, the formulations of the present invention are contained in such oral dosage forms at a concentration ranging from about 0.5 to about 90%, based on the total composition mass, in an amount sufficient to provide a given unit dose. Exists.

  For oral administration, tablets containing various excipients such as lactose, microcrystalline cellulose, sodium citrate, calcium carbonate and calcium phosphate, and various disintegrants such as starch and preferably potato or tapioca or corn starch Alginic acid and certain complex silicates can be used with binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, sucrose, gelatin, starch and acacia gum. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc or similar types of combinations can also be used as fillers in soft and hard gelatin capsules, which can include lactose, lactose and high molecular weight polyethylene glycols. . If aqueous suspensions and / or elixirs are desired for oral administration, the essential active ingredients are various sweetening or flavoring agents, coloring substances or dyes, and if necessary emulsifiers and / or water, ethanol, Can be combined with propylene glycol, glycerin and various similar combinations thereof.

  In the case of suspensions, syrups or dry syrups, suitable excipients are in particular the excipients normally used for producing suspensions, syrups or dry syrups. Particularly suitable for the present invention are excipients, such as thickeners and / or binders, which make it possible to produce a thick base. Examples of thickeners and binders according to the invention are xanthan gum, substituted cellulose, polyvinylpyrrolidone (polyvidone type), sheet silicate, alginate or alginic acid. If desired, a mixture of two or more different thickeners can be used. The proportion of this thickener depends on the predetermined viscosity or consistency to be applied to the dry syrup, syrup or suspension. The proportion of xanthan gum, usually based on dry syrup, syrup or suspension, is in the range of 0.1-1% by weight. The proportion of substituted cellulose depends on the viscosity level of the cellulose and is usually in the range of 0.1-10% by weight, based on dry syrup, syrup or suspension. Examples of substituted celluloses according to the invention that can be enumerated are carboxymethylcellulose, ethylcellulose or methylcellulose or hydroxypropylcellulose.

The proportion of polyvinylpyrrolidone (polyvidone type) is usually 0.1 to 10% by mass, preferably 1 to 5% by mass, more preferably 2% by mass, based on dry syrup, syrup or suspension. Sheet silicates such as Veegum or bentonite can be used alone or in combination with water-soluble thickeners. Accordingly, the total proportion of thickener is advantageously in the range of 0.1 to 7% by weight, based on dry syrup, syrup or suspension. Alginate or alginic acid is usually added at a ratio of 0.1 to 10% by mass based on dry syrup, syrup or suspension. Furthermore, pharmaceutical excipients that can be used are insoluble crosslinked polyvinylpyrrolidone (crospolyvidone) and microcrystalline cellulose. In this case, the formation of airborne precipitates and interference with the aggregation of the formulation particles are observed. The ratio of crospolyvidone to the individual active ingredient units is advantageously in the range from 1: 1 to 0.5: 1 (mass basis). Microcrystalline cellulose is also suitable for this purpose, and the proportion used is usually in the range from 0.5 to 5% by weight, based on dry syrup, syrup or suspension.

  Other suitable excipients that may be present in the dry syrups, syrups or suspensions of the present invention are, for example, flavoring substances (eg, fragrances and sweeteners), buffer substances, preservatives or other emulsifiers. A fragrance | flavor is normally added in the ratio of 0.05-1 mass%. Examples of other flavoring substances are acids such as citric acid, sweeteners such as monoammonium glycyrrhizinate, saccharin, erythritol, aspartame, sodium cyclamate or maltol, which are added depending on the intended intended result. The In a preferred embodiment of the present invention, erythritol as the sweetener is present in the dry syrup in an amount of up to 90% by weight, preferably 60-80%, more preferably 65-75%, most preferably 75% by weight. To do. It is also preferable to add aspartame as the second sweetener. The amount of aspartame is preferably 1-10% by weight, more preferably 5% by weight. Furthermore, it is also preferable to add monoammonium glycyrrhizinate in an amount in the range of 0.05 to 2% by mass, preferably 0.1 to 1% by mass. Examples of emulsifiers are lecithin, sodium lauryl sulfate, Tween or Span. These are usually added at a ratio of 0.01 to 5% by mass. Preferably, sodium lauryl sulfate is used in an amount of 0.1 to 2.5% by mass, more preferably 1% by mass. It is also possible to add preservatives such as benzoic acid, its salts, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, sorbic acid or its salts. The proportion depends on the preservative used and is usually in the range of 0.1 to 4% by weight, based on dry syrup, syrup or suspension.

The oral dosage form is made by methods known to those skilled in the art. When preparing a restorable powder (dry syrup), a mixture is preferably made of the formulation with a thickener and / or binder and, if appropriate, further excipients. This reconstituted powder mixture is mixed with an appropriate amount of water just prior to administration.
In particular, dry syrup can be produced according to the following steps (see FIG. 1):
a) dissolving the water-soluble active compound, preferably epinastine, quinine-hydrochloride or sulfate, or acetaminophen in a solvent;
b) a step of immersing a porous absorbent in the solution obtained in the step a) to allow the absorbent to absorb the pharmacologically active compound;
c) removing the solvent;
d) mixing at least one bitter-masking agent with at least one pharmaceutically acceptable surfactant;
e) adding the coating mixture obtained in step d) to the particles obtained in step c); and
f) A step of granulating the preparation obtained in the step e) together with other components according to a conventional method.

The formulations and dosage forms of the present invention can be treated and prevented using the epinastine, quinine and acetaminophen, all diseases, especially allergies, pain, especially pain caused by chronic pain and inflammation Can be used for the treatment and prevention of migraine, asthma, rhinitis, conjunctivitis, skin diseases, and / or bronchitis, preferably allergies. The dosage form comprises the particular active ingredient, usually in a dose to treat the particular disease.
Accordingly, the present invention provides the use of the above-described preparations of the present invention, i.e. allergies, pain, especially pain due to chronic pain and inflammation, migraine, asthma, rhinitis, conjunctivitis, skin diseases and / or bronchitis, preferably Relates to its use in the manufacture of a medicament for the prevention and / or treatment of allergies. Furthermore, the present invention also provides a method for preventing and / or treating allergies, pain, especially pain due to chronic pain and inflammation, migraine, asthma, rhinitis, conjunctivitis, skin diseases and / or bronchitis, preferably allergies In this regard, the method includes administering a therapeutically effective amount of a formulation or oral dosage form to a subject in need of such treatment.

The present invention will be described below with reference to examples, but the present invention is not limited to these examples. In these examples, unless otherwise stated, all parts should be understood to be% by mass.
Example 1: Dry syrup

Preparation :
The dry syrup is prepared as follows (see FIG. 1).
The epinastine hydrochloride was dissolved in ethanol (Step 1). The obtained solution was added to the porous absorbent magnesium aluminometasilicate and mixed well (step 2). Subsequently, ethanol was removed by heating the mixture to 80 ° C. (step 3).
To prepare the coating mixture, the surfactant and medium chain fatty acid triglycerides were mixed thoroughly (Step 4).
The coating mixture from step 4 was added to the powder obtained in step 3 and mixed well.
Finally, this obtained preparation was granulated with the above-mentioned other components according to a conventional method.
Example 2: Sample (powder formulation) flavor The following formulation was prepared according to Example 1 and subsequently tested for its flavor:
Sample 1: Epinastine hydrochloride Sample 2: Epinastine hydrochloride absorbed in magnesium aluminometasilicate Sample 3: Sample 2 covered with coating mixture

Results : Sample 1 and Sample 2 were clearly more bitter than Sample 3. This coating mixture significantly suppresses the bitter taste of epinastine hydrochloride.
Example 3: Sample Flavor The following formulation was prepared according to Example 1 and subsequently tested for its flavor:
Sample 4: Epinastine Hydrochloride Sample 5: Epinastine Hydrochloride Dry Syrup + Basic Formula to Conceal Bitterness Sample 6: Epinastine Hydrochloride Dry Syrup that does not Conceal Bitterness

Results : Sample 4 is even more bitter and sample 6 is more bitter than sample 5. This coating mixture significantly suppresses the bitter taste of epinastine hydrochloride.
Example 4 : Determination of oil, fat, wax or fatty alcohol content:

Result : Sample 10 became a slurry after the mixing step. Therefore, it is considered that the amount of the oil is excessive. On the other hand, sample 7 was clearly more bitter than samples 8 and 9. In this case, the appropriate amount of oil containing the surfactant is considered to be in the range of 0.5 to 1.2 relative to the amount of the drug-carrying absorbent. However, the appropriate amount of oil containing the surfactant depends on the absorbent capacity of the absorbent.
Example 5: Study on surfactant content

Results : Sample 11 is clearly more bitter and sample 12 is slightly more bitter than samples 13-15. These results suggest that the appropriate content of the surfactant in the oil is in this case a value exceeding 3% with respect to the oil.

It is a process flow diagram which shows the manufacturing process of dry syrup.

Claims (13)

a) a water-soluble pharmacologically active compound absorbed in the porous absorbent, and
b) containing a coating covering the drug-carrying porous absorbent, characterized in that the coating comprises a mixture of a pharmaceutically acceptable surfactant and a pharmaceutically acceptable bitter-masking agent, A formulation comprising:
The pharmacologically active compound is epinastine hydrochloride in a range of 2.5 to 5% by mass;
The porous absorbent is magnesium aluminometasilicate, anhydrous silicic acid, calcium carbonate, hydrated silicon dioxide, magnesium silicate, medical carbon, silica gel, microcrystalline cellulose, starch, aluminum hydroxide gel, aluminum hydroxychloride, magnesium aluminosilicate, Selected from the group consisting of sodium carboxymethyl starch or mixtures thereof;
The bitterness-masking agent is linseed oil, tung oil, soybean oil, peanut oil, sesame oil, palm oil, milk fat, rapeseed oil, corn oil, carnauba wax, cottonseed oil, esterified corn oil, orange oil, almond oil, safflower oil fatty acid , Tocopherol acetate, chamomile oil, hydrogenated soybean oil, stearic acid, safflower oil, hard fat, camellia oil, nuka oil, castor oil, coconut oil, olive oil, petrolatum, octyldecyl triglyceride, cacao butter, medium chain fatty acid triglyceride, squalane Selected from the group consisting of oleic acid, clove oil, white beeswax, malt oil, stearyl alcohol or mixtures thereof;
The surfactant is alkyl allyl polyether alcohol, fatty acid sucrose ester, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, fatty acid propylene glycol ester, lauryl sulfate, stearate, fatty acid sorbitan ester, Polyethylene glycol ester of fatty acid, polyoxyethylene glycerol ester of fatty acid, glycerol ester of fatty acid, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitol ester of fatty acid, polyoxyethylene alkyl allyl ether, alkyl allyl sulfonate, coconut fatty acid Selected from the group consisting of diethanolamide, or polyoxyethylene sorbitan esters of fatty acids, or mixtures thereof;
The mass ratio of the coating to the absorbent carrying the drug is in the range of 0.7 to 0.9, and the content of the surfactant in the coating is in the range of 9 to 10% by mass. Feature, formulation.   An oral dosage form characterized in that it comprises the formulation of claim 1.   The oral dosage form according to claim 2, wherein the dosage form is a liquid.   The oral dosage form according to claim 2, wherein the dosage form is dry syrup.   Use of the formulation according to claim 1 in the manufacture of a pharmaceutical formulation for the prevention and / or treatment of allergies, pain, migraines, asthma, rhinitis, conjunctivitis, skin diseases and / or bronchitis.   Use according to claim 5, wherein the pain is chronic pain and pain caused by inflammation.   Use of the preparation according to claim 1 in the manufacture of a pharmaceutical formulation for preventing and / or treating allergies.   Allergy, pain, migraine, asthma, rhinitis, conjunctivitis, skin disease comprising a therapeutically effective amount of the formulation of claim 1 or the oral dosage form of any one of claims 2-4 And / or a pharmaceutical composition for preventing and / or treating bronchitis.   The pharmaceutical composition according to claim 8, wherein the pain is chronic pain and pain caused by inflammation.   A pharmaceutical composition for preventing and / or treating allergies, comprising a therapeutically effective amount of the preparation according to claim 1 or the oral dosage form according to any one of claims 2 to 4. A method for producing the formulation of claim 1,
a) dissolving a water-soluble pharmacologically active compound in a solvent;
b) a step of immersing the porous absorbent in the solution obtained in step a) and allowing the absorbent to absorb the pharmacologically active compound;
c) removing the solvent;
d) mixing the bitter-masking agent with a pharmaceutically acceptable surfactant to obtain a coating; and
e) adding the coating of step d) to the particles obtained in step c).   A method for producing an oral dosage form, characterized in that the formulation according to claim 1 is mixed with at least one pharmaceutically acceptable inert excipient. A method for producing a dry syrup comprising the formulation of claim 1,
a) dissolving a water-soluble pharmacologically active compound in a solvent;
b) a step of immersing the porous absorbent in the solution obtained in step a) and allowing the absorbent to absorb the pharmacologically active compound;
c) removing the solvent;
d) mixing a bitter-masking agent with a pharmaceutically acceptable surfactant to obtain a coating;
e) adding the coating of step d) to the particles obtained in step c); and
f) A step of granulating the preparation obtained in step e) together with other ingredients according to a conventional method,
A method comprising the steps of:

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