KR100466897B1 - Flavor Improvement of Pharmaceutical Active Ingredients - Google Patents

Abstract

The present invention relates to a method for improving the taste of a solid composition comprising at least one active ingredient.

Description

Improvement of flavor of pharmaceutically active ingredient

The present invention relates to a flavor profile of a solid composition such as a tablet comprising, for example, an active substance or a mineral substance, namely a method for improving organoleptic sensation in the mouth as well as the actual flavor itself.

Polyols and polyol mixtures are widely used as additives and excipients which do not cause caries, especially in pharmaceutically active substances, chewable tablets, lozenges and other products of the pharmaceutical industry, and as compressed products in the food industry. Used. Polyols are generally produced by hydrogenating basic sugars. They can be obtained in solid form by crystallization or spray-drying. A particular advantage of some polyols is that they are suitable for direct compression without additional auxiliaries and additives.

Known polyols, mannitol, lactitol, isomaltol, xylitol have low hygroscopicity and are difficult to be tableted, so tablet hardness is low, scale-off occurs, and tablet friability is large. In solid compositions, excipients are mostly used only in small amounts, and it is fundamentally advantageous to achieve high tablet hardness, since the active compounds can significantly reduce the tablet hardness and thus cannot tablet the desired pharmaceutical composition.

Lactitol, isomalthol and xylitol are rarely used in the manufacture of compressed articles, while mannitol is widely used in pharmaceutical compositions.

However, mannitol generally needs to be wet granulated with the rest of the pharmaceutical composition before compacting, so using mannitol complicates the working procedure. In addition, mannitol, which can be readily refined, is commercially available, but it is not possible to obtain satisfactory tablet hardness compared to sorbitol.

Sorbitol, in particular sorbitol obtained through spray-drying, has a very good tablet hardness. In addition, the compressed article produced is particularly smooth in surface. According to the paper (Basedow et al.), Tablets containing calcium carbonate can be prepared by spraying together with spray-dried or crystalline sorbitol. However, sorbitol has higher hygroscopicity than other polyols, and its use is limited. In this regard, there is also a lack of literature demonstrating that the use of sorbitol or other polyols substantially improves the flavor profile of the composition.

In the case of liquid formulations, as well as in the manufacture of pharmaceutical formulations to be administered orally, the flavor profile felt by the user is largely a problem. Especially for chewable tablet antacids, it is undesirable to have a chalky taste. Efforts have been made to eliminate this chalky taste with various additives, but have been relatively unsuccessful. Known antacids have a slimy, undesirable taste, such as chalk, in the mouth, which can be masked slightly with conventional additives, but when chewed, this taste is aggravated again.

Another problem that is widespread in active substances is extremely bitter taste. Efforts have been made to mask this taste from particularly bitter or chalky active substances, but adding flavors or fragrances has not been effective. It would also be possible to coat tablets comprising such active materials, but this method is not suitable if the purpose is to chew the tablets and quickly absorb the active materials through the mucous membranes of the mouth.

In addition, the surfaces of the sucking tablets, such as those that are taken when the throat hurts, must meet certain requirements. A requirement at this time is that the tablet surface remains smooth and does not gradually become rough during sucking.

In addition, sugar-containing tablets and especially chewable tablets are currently used in the field of supplements (vitamins and mineral foods). In particular, for tablets that provide minerals, the excipient is rarely added and the flavor profile depends on the minerals in question.

In addition, in the preparation of solid compositions, attempts to use immediately compressible active materials (DC active materials) have been actively made in order to lower production costs.

It is therefore an object of the present invention to provide a method which, on the one hand, improves the flavor profile of the solid composition and at the same time plays a positive role in the sensory sensation in the mouth for the product obtained.

The inventors have described the composition (comprising one or more active ingredients, obtained through simultaneous spray-drying or fluid-bed granulation with one or more polyols) to produce a solid dosage form, the flavor of the solid composition. We found that we could improve the profile.

Accordingly, the present invention relates to a process for the preparation of a DC active ingredient which can improve the flavor profile of a solid composition comprising at least one active ingredient, comprising at least one active ingredient, together with at least one polyol A method characterized in that the composition obtainable through simultaneous spray-drying or fluid-bed granulation is compressed to produce a solid dosage form. The total amount of polyol used is such that it is 10 to 90% by weight, in particular 25 to 75% by weight, relative to the powdered component mixture prepared according to the process of the invention.

The essential compositions of the present invention comprise dissolving one or more polyols in water, dissolving or suspending one or more active ingredients in a solvent, and the resulting water-soluble mixture in airflow at a temperature of 120 to 300 ° C., preferably 140 to 190 ° C. Can be obtained by spraying. Alternatively, the obtained water-soluble mixture can be fluidized in the air stream at a temperature of 40 to 120 ° C.

Before simultaneous spray-drying or fluid-bed granulation, the flavor improver and, if appropriate, the colorant, can be added to the aqueous mixture. Suitable flavor improvers are, in particular, natural or synthetic sweeteners from the group consisting of saccharin, aspartame (R), acesulfame-K, neohesperidin DC, sucralose, taumartin or steviosides. Polyols that can be used include polyols from the group consisting of sorbitol, mannitol, lactitol, isomalthol, maltitol, erythritol or xylitol. They are possible from 10 to 90% by weight, in particular from 25 to 75% by weight of the obtained product.

The present invention therefore also relates to solid compositions with improved flavor profiles produced through the process according to the invention. Such compositions comprise, on the one hand, from 0.1 to 90% by weight, in particular from 25 to 75% by weight of minerals from the group of physiologically acceptable Ca, Mg, Na, K, Fe and Zn salts, if appropriate trace elements, and one or more vitamins ( ) And one or more active ingredients which may be bitter.

The composition prepared by the method according to the invention may comprise one or more pharmaceutically active ingredients. Such active ingredients include, in particular, antacids, antiallergic agents, analgesics, hormones, steroids, estrogens, contraceptives, nasal decongestants, H ₁ and H ₂ antagonists, β ₂ stimulants, vasodilators, blood pressure lowering agents, anti-infective agents, laxatives Antitussives, bronchodilators, sore throat cure, bismuth and salts thereof, antifungals, antibiotics, stimulants (eg amphetamines) alkaloids, oral hypoglycemic agents, diuretics, cholesterol-lowering agents, various pharmaceutical actives or other active agents Combinations are possible. Such active materials can range from 0.1 to 70% by weight.

The active substance may be present as coated particles, liposomes or microparticles. As the coating agent, materials commonly used in pharmacy may be used. The active material preferably has a particle size of 0.1 to 800 mu m and a bulk density of 0.15 to 1 g / cm 3.

Regarding the above weight percentages, it should be understood, of course, that the sum of the materials used does not exceed 100%.

The term polyol is a chemical formula

CH ₂ OH- (CHOH) _n -CH ₂ OH

(Wherein n is 2 to 6, preferably 3 to 4) sugar alcohols and dimer anhydrides thereof, in particular C ₁₂ H ₂₄ O ₁₁ .

In particular, the term polyol means hexitols such as sorbitol and mannitol, pentitols such as xylitol, but other C ₁₂ polyalcohols such as C ₄ polyalcohols such as erythritol, lactitol or maltitol are possible. However, the term polyol should be understood as a suitable carbohydrate.

The mixture used for spray-drying is at least one polyol aqueous solution. At temperatures up to 80 ° C., it is preferable to mix the at least one polyol solution with at least one preferred active ingredient (s) solution or suspension in a desired proportion so that the solids content is about 10 to 90% by weight, in particular 50 to 72% by weight. desirable. Spraying is carried out using an atomizing nozzle, in particular a centrifugal atomizer, in a dry air stream which is heated to a temperature of 120 to 300 ° C., preferably 140 to 190 ° C. and introduced into centrifugal force. In the fluidized bed, the amount of polyol solution to be fed is adjusted with the amount of hot air so that the mixture of the obtained powdered material is dried to a water content of about 0.1 to about 1% by weight. In any case, the moisture content should be 1% by weight or less.

Fluid bed granulation is described, for example, in P. It is carried out as described in Grassmann, F. Widmer "Einfuhrung in die thermische Verfahrenstechnik" [Introduction to Thermal Process Technology].

Through certain preparation methods for spraying aqueous solutions, for example, citric acid, sweeteners, in particular acesulfame-K, aspartame ^(R) , saccharin, cyclamate and sucralose, neohesperidin DC, dyes and pharmaceutical activity Water-soluble and non-water-soluble additives such as substances (eg, analgesics, antacids, etc.), vitamins and, if appropriate, trace elements, may be allowed to be uniformly distributed in the solid compositions or mixtures according to the invention and the tablets produced therefrom. .

Optionally added binders are familiar to those skilled in the art and increase the hardness of the composition. Preferred binders are cellulose derivatives, in particular hydroxypropyl methylcellulose, carboxymethylcellulose or starch.

Such polyol compositions have a series of features that are advantageous for tableting.

Surprisingly, the compositions of the present invention can be used in accordance with the methods of the present invention to obtain solid compositions, in particular tablets, with greatly improved taste profiles and sensory sensations in the mouth. At the same time, this advantageous feature gives rise to the possibility of directly compressing the composition obtained through simultaneous spray-drying or fluid-bed granulation. Thus, immediately compressible active material compositions (DC active materials) are obtained.

Using a composition with a high mineral content of up to 90%, on the one hand can greatly improve the tableting properties, and on the other hand can significantly lower the wear resistance in the packaging of the tablets produced. In addition, using the composition according to the present invention, tablets with smoother surfaces and harder surfaces can be obtained at the same pressure as applied to known polyol-containing compositions.

In general, since chalky or slippery flavors are masked well, improved sensory sensation in these mouths is not only noticed initially but also during chewing or sucking. Surprisingly, these mineral tablets do not only improve the flavor profile. The composition to which the extremely bitter active compound is added also makes it hard to recognize a bitter flavor, and the taste improves significantly.

The following examples are intended to explain the invention in detail, but the scope of the invention is not limited thereto.

Example

Example 1

Antacid tablets

Composition of the tableting mixture:

Calcium Carbonate 65.50%

Carrion Instant 28.19%

Carrion Powder p300 4.70%

Chlorophyllin 100% 0.01%

Neohesperidin DC 0.10%

Peppermint Naefco 0.30%

(Product made in Firmenich)

Magnesium Stearate 1.00%

Mechanical preparation of the mixture:

Calcium carbonate and sorbitol (Carion Instant and Carion Powder p300) were mixed in a turbula mixer for 5 minutes. Chlorophyllin, neohesperidine DC and peppermint flavor were added successively and mixing continued for 5 minutes. The mixture was sieved with a mesh size of 1 mm. Magnesium stearate was added to the filtered mixture with a sieve of 250 μm mesh size and mixing continued for another 5 minutes. The resulting mixture was purified.

Preparation of the mixture by simultaneous spraying:

In the above manner, calcium carbonate, sorbitol, neohesperidin DC and chlorophyllin were sprayed simultaneously. Simultaneously sprayed material and fragrances were placed in a turbula mixer, magnesium stearate was added to the mixture by a sieve of 250 μm mesh size and the whole was mixed for 5 minutes. The resulting mixture was purified.

result:

Example 2

Painkiller tablets

Composition of tableting material:

Acetyl Salicylic Acid (ASA) 74.0%

Sorbitol Content 24.5%

(Mixed instant product or sprayed with ASA)

Acesulfame K 0.5%

Magnesium Stearate 1.0%

Tableting and taste comparison

Preparation of mechanical mixtures:

The ASA was ground to finely powder and ground with sorbitol instants in a turbula shaking mixer containing micronized sweetener ASK. The mass was filtered off with a 1 mm sieve, remixed with magnesium stearate, and then purified.

Preparation of Co-Sprayed Tablet Material:

A portion of the finely powdered and ground ASA (about 5%) was introduced into the fluid phase and the remainder was dispersed in the sorbitol solution at a ratio of about 1: 1. Stirred to maintain dispersion and sprayed directly to the fluidized bed with the sweetener ASK while evaporating water.

The relatively fine spray granules thus formed were mixed with 1% magnesium stearate as a lubricant. The resulting mixture was immediately purified.

result:

Example 3

Vitamin c tablets

Ascorbic acid 87.7%

Sorbitol 10.0%

Orange flavor 0.7%

Acesulfame K 0.6%

Magnesium Stearate 1.0%

Preparation of mechanical mixtures:

Fine crystalline ascorbic acid was ground directly with sorbitol instants (0.3 mm or less granules), sweeteners and fragrances in a turbula shaking mixer. Then, magnesium stearate as a lubricant was sieved and mixed therein.

Preparation of Simultaneous Spray Tableting Materials:

Ascorbic acid, sorbitol and sweeteners were dissolved in water at 40 ° C. with a solids content of about 40% and sprayed onto a bed of monolithic crystals (15% by weight) of the fluidizing device. Spray granules were mixed with the same fragrance and magnesium stearate as used for the above tableting.

result:

Claims (16)

A method for improving the flavor profile of a solid composition comprising at least one active substance, Co-spraying by comprising one or more active substances, dissolving one or more polyols or carbohydrates in water, dissolving or suspending one or more active substances in a solvent and spraying the resulting aqueous mixture at a temperature of 120 to 300 ° C. in the air stream. Obtained by drying, or by fluid bed granulation by dissolving one or more polyols or carbohydrates in water and dissolving or suspending one or more active substances in a solvent and fluidizing the resulting aqueous mixture at a temperature of 40-120 ° C. in air stream. Compressing the composition, which is immediately compressed into a solid dosage form. The method of claim 1, The composition obtained through simultaneous spray-drying or fluid-bed granulation is a composition of the immediately compressible active substance. The method according to claim 1 or 2, The composition further comprises a flavor improver. The composition of claim 1, comprising at least one active material and at least one polyol. The method of claim 4, wherein Wherein said composition further comprises at least one natural or synthetic sweetener. The method of claim 4, wherein And wherein said polyol is selected from the group consisting of sorbitol, mannitol, lactitol, isomitol, maltitol, erythritol and xylitol. Solid composition with improved flavor profile prepared by the process according to claim 1. The method of claim 7, wherein And wherein said solid composition further comprises from 10 to 90% by weight minerals from the group of physiologically acceptable Ca, Mg, Na, K, Fe and Zn salts. The method of claim 7, wherein The solid composition may include analgesics, antacids, antiallergic substances, hormones, steroids, estrogens, contraceptives, nasal decongestants, H ₁ and H ₂ antagonists, β ₂ stimulants, vasodilators, blood pressure lowering agents, anti-infective agents, laxatives, antitussives Solid composition comprising at least one active substance in the group consisting of bronchodilators, sore throat pain, bismuth and salts thereof, antifungals, antibiotics, alkaloids, oral hypoglycemics, diuretics, cholesterol-lowering agents . The method of claim 7, wherein Solid composition, characterized in that the solid composition comprises 0.1 to 70% by weight of one or more drugs. The method of claim 3, Wherein said composition further comprises a colorant. The method of claim 5, Said sweetener is selected from the group consisting of saccharin, aspartame ^(R) , acesulfame-K, neohesperidin DC, sucralose, taumartin and steviosides. The method of claim 4, wherein Wherein said composition further comprises at least one colorant. The method of claim 8, Solid composition, characterized in that the solid composition further comprises a trace element. The method of claim 8, Solid composition, characterized in that the solid composition further comprises one or more vitamins. The method of claim 8, And wherein said solid composition further comprises one or more active substances which may be bitter.