阅读说明：本技术 Hmc方法中使用的涂覆材料 (Coating material for use in HMC process ) 是由 德克·洛赫曼 塞巴斯蒂安·雷耶 迈克尔·斯蒂尔 安德·尔齐默 沙拉雷·萨拉尔·贝赫扎迪 于 2018-10-22 设计创作，主要内容包括：本发明涉及一种用于在热熔涂覆方法中使用的涂覆材料,所述材料包含一种或多种聚甘油脂肪酸作为主要成分,每种聚甘油脂肪酸通过包含二个至八个甘油基单元的直链或支链聚甘油与一种或多种脂肪酸的完全或部分酯化获得,每种脂肪酸包含6个至22个碳原子。(The invention relates to a coating material for use in a hot-melt coating process, said material comprising as main component one or more polyglyceryl fatty acids, each polyglyceryl fatty acid being obtained by the complete or partial esterification of a linear or branched polyglyceryl comprising two to eight glyceryl units with one or more fatty acids, each fatty acid comprising 6 to 22 carbon atoms.)

1. A coating material for use in a hot melt coating process,

it is characterized in that

One or more polyethylene glycol fatty acid esters as a main component, each polyethylene glycol fatty acid esterBy passingOf linear or branched polyglycerols comprising two to eight glycerol units with one or more fatty acidsFull or partial esterificationObtained, each fatty acid contains from 6 to 22 carbon atoms.

2. The coating material according to claim 1,

it is characterized in that the preparation method is characterized in that,

the fatty acid on which the polyglycerol fatty acid ester or esters are based is saturated or unbranched or is saturated and unbranched.

3. Coating material according to one of the preceding claims,

it is characterized in that the preparation method is characterized in that,

based on said one or more polyglyceryl fatty acid estersThe fatty acidHaving 16, 18, 20 or 22 carbon atoms.

4. Coating material according to one of the preceding claims,

it is characterized in that the preparation method is characterized in that,

the detection of the individual polyglycerol fatty acid ester or esters by dynamic differential calorimetry of the heat flow gives correspondingly only an endothermic minimum during heating and correspondingly only an exothermic maximum during cooling.

5. Coating material according to one of the preceding claims,

it is characterized in that

A stable subcellular form of the one or more polyglyceryl fatty acid esters below the coagulation temperature, the subcellular form having a substantially constant lamellar distance with a bragg angle maintained at 40 ℃ for at least 6 months as evaluated using a WAXS analysis.

6. Coating material according to one of the preceding claims,

it is characterized in that

A stable subcellular form of the one or more polyglyceryl fatty acid esters below the freezing temperature, the subcellular form having a substantially constant thickness of crystallites of the lamellar structure maintained at 40 ℃ for at least 6 months according to a SAXS analysis evaluated using the scherrer equation.

7. Coating material according to one of the preceding claims,

it is characterized in that

At least one polyglyceryl fatty acid ester from the group consisting of:

PG (2) -C18 full ester, PG (2) -C22 partial ester having a hydroxyl value of 15 to 100, PG (2) -C22 full ester, PG (3) -C16/C18 partial ester having a hydroxyl value of 100 to 200, PG (3) -C22 partial ester having a hydroxyl value of 100 to 200, PG (3) -C22 full ester, PG (4) -C16 partial ester having a hydroxyl value of 150 to 250, PG (4) -C16 full ester, PG (4) -C16/C18 partial ester having a hydroxyl value of 150 to 250, PG (4) -C16/C18 full ester, PG (4) -C18 partial ester having a hydroxyl value of 100 to 200, PG (4) -C22 partial ester having a hydroxyl value of 100 to 200, PG (6) -C16/C6 partial ester having a hydroxyl value of 200 to 300, PG (6) -C16/C18 partial ester, PG (100 to 200) partial ester having a hydroxyl value of 100 to 200, wherein the two fatty acid residues thereof are different in number and wherein PG (3) -C22) is a fatty acid residue, those with a lower number of carbon atoms constitute from 35% to 45% and those with a higher number of carbon atoms constitute correspondingly from 55% to 65% in a complementary manner, and the full esters listed preferably have a hydroxyl number of less than 5.

8. Coating material according to one of the preceding claims,

it is characterized in that

Less than 300mPa at 80 DEG C^.s, preferably less than 200mPa^.s, particularly preferably less than 100mPa^.s。

9. Coating material according to one of the preceding claims,

it is characterized in that

A freezing temperature of less than 75 ℃, preferably between 43 ℃ and 56 ℃, of the individual polyglycerol fatty acid ester or esters.

10. Coating material according to one of the preceding claims,

it is characterized in that the preparation method is characterized in that,

the contact angle determined for determining the hydrophobicity of the individual polyglycerol fatty acid ester or esters has a deviation of less than 10 ° from the initial value after 16 weeks at 40 ℃ and at 20 ℃.

11. Coating material according to one of the preceding claims,

it is characterized in that

Mixtures of synthesized polyglycerol fatty acid esters, which can be obtained by esterification reactions that differ from each other by the reactants used, respectively, as a main component.

12. Coating material according to one of the preceding claims,

it is characterized in that

A polyglycerol fatty acid ester content of at least 98 wt.%.

13. Coating material according to one of the preceding claims,

it is characterized in that

A solvent-free composition or a surfactant-free composition, or a solvent-free and surfactant-free composition.

14. A combination of a coating material with a composition according to one of the preceding claims and a dispersing material,

it is characterized in that the preparation method is characterized in that,

the coating material has a hollow spherical heteromorphic shape obtained by spraying a melt thereof, the hollow spherical heteromorphic shape having an internal cavity containing the dispersed material.

15. In combination in accordance with claim 14, wherein,

it is characterized in that the preparation method is characterized in that,

the dispersion material has at least one active pharmaceutical ingredient.

16. The combination according to claim 14 or 15,

it is characterized in that the preparation method is characterized in that,

the dispersion material consists of crystals of one or more active pharmaceutical ingredients.

17. A hot-melt coating method in which a dispersion material is coated with a coating material to form a product from surface-stabilized individual parts,

it is characterized in that the preparation method is characterized in that,

the coating material has a composition according to one of claims 1 to 13.

18. The hot melt coating method according to claim 17,

it is characterized in that the preparation method is characterized in that,

the product having a combination according to one of claims 14 to 16.

19. The hot melt coating method according to claim 18,

it is characterized in that the preparation method is characterized in that,

the active pharmaceutical ingredient is thermally unstable and has more than 98% of its initial effective activity after coating and subsequent cooling to ambient temperature.

20. The hot melt coating method according to one of claims 17 or 18,

it is characterized in that the preparation method is characterized in that,

the temperature of the gas or gas mixture used for spraying the coating material during spraying is only 3 ℃, preferably only 1 to 2 ℃ below the solidification temperature of the coating material.

Technical Field

Compositions for coating materials used in Hot-Melt coating processes (Hot-Melt coating process, abbreviated to HMC process) are proposed, which coating materials can also be used in the production of pharmaceuticals.

The HMC process offers advantages over other coating methods. In the HMC process, a coating material is sprayed onto a dispersion material (for example solid particles as a dispersant in a gas or gas mixture), wherein the dispersion material is usually provided in the form of a fluidized bed. Dispersed material here refers to material separated from the surrounding medium by a phase interface. In contrast to other methods, the viscosity of the melted HMC coating is sufficiently low for the method step of spraying that no solvent (such as, for example, water) needs to be used to reduce the viscosity. An energy-consuming and time-consuming drying step can thus also be dispensed with. The use of a solventless HMC coating also significantly reduces the risk of the dispersed material undesirably partially dissolving in the coating material during the coating process. The HMC process has been frequently used in the food industry. For the production of pharmaceuticals, it is often necessary to provide particles, crystals or generally granules (more generally also including, for example, droplets) of a dispersed material with one or more pharmaceutical active ingredients with a coating in order to mask, for example, an unpleasant taste, to protect the active ingredient from environmental influences (such as, for example, moisture or UV radiation) or to influence the rate of release of the active ingredient. In order to be able to use the HMC process also in pharmaceutical production, HMC coatings have to meet specific requirements. In particular, they must remain stable for a long period of time and their physicochemical properties should change only within very narrow limits over the course of several years, as slowly as possible, in order to be able to ensure constant release kinetics or adequate protection of the pharmaceutically active ingredient over a long storage time. Any method of applying a solvent-free coating material as a solution to a dispersion material by spraying the coating material is referred to herein as a hot melt coating method or an HMC method, the size of the individual portions of the dispersion material being substantially freely selectable. The coating material used here is also referred to below as HMC coating or HMC coating material.

Background

Meanwhile, various HMC coatings are known, which have been developed mainly for specific pharmaceutically active ingredients. WO 2014/167124a1 explicitly points out the following problems: triglycerides, such as tripalmitin or tristearin, are polymorphic and therefore accordingly exist simultaneously as crystalline unstable alpha-variants, and as metastable or stable beta-variants, and may transition from one variant to the other. These variants are distinguished here in particular by the thickness of the lamellar stacked crystalline subunits, also referred to as subcellular units. For an alpha-variant such as glyceryl tristearate, a layer with an average of 6 layers per subcellular unit can be determined under certain conditions, after complete conversion to the beta-variant, with an average of 10.5 layers per subcellular unit and an increase in crystal thickness of about 67%. The fact that the mathematically expected increase of 75% was not reached may be due to the fact that: the individual sheets of the β -variant have a denser lamellar stack due to the resulting tilted position relative to the α -variant (see D.G. lopes, K.Becker, M.Stehr, D.Lochmann et al, in Journal of Pharmaceutical Sciences104:4257-4265, 2015). The α -modification has faster formation kinetics than the β' -modification and the β -modification at temperatures which are kept as low as possible during spraying in the HMC process, and therefore results after the application of the dispersion material containing the active substance is completed with the HMC process, which, however, undesirably rearranges itself into a more stable β -modification during storage with an increase in the volume of the coating known as "blooming", which is also associated with macroscopic fractures. According to WO 2014/167124a1, a solution to the problem in question is formed by the addition of a polysorbate (i.e. a non-ionic surfactant), wherein the polysorbate component is 10% -30% of the coating material. In fact, the mixture of triglycerides and polysorbates does not appear to have the problem of "blooming", but the mixture separates over a long time, so that it is not possible to exclude the change in the release kinetics which would have been substantially stable in a pharmaceutical formulation.

US 5,891,476 discloses compositions with carnauba wax, in order to have no polymorphism. However, the high melting temperature of carnauba wax between 82 ℃ and 86 ℃ is disadvantageous. The disclosed compositions are therefore not suitable for thermally unstable active ingredients, since the temperature in the HMC process will have to be partly 100 ℃ or higher, and a further disadvantage is that the wax, which solidifies very fast, easily settles in the lines and nozzles of the HMC plant when the temperature is lowered, and thus causes clogging of the plant.

US 2010/0092569 a1 discloses the intercalation of a silicate powder adsorbate with an active ingredient into a molten lipid matrix, and subsequent spraying and cooling to produce coated particles, wherein the lipid matrix consists of triglycerides of saturated even numbered fatty acids having 16 to 22 carbon atoms per fatty acid and 3% of an emulsifier, in order to ensure uniformity of dispersion of the active ingredient in the lipid matrix. This production method also requires temperatures above 70 ℃ and is therefore not suitable for temperature-sensitive active ingredients. The disclosed method is used for producing animal food; the release kinetics of the active ingredient are of vital importance for pharmaceutical products for human use and are not addressed in the mentioned publications.

Disclosure of Invention

Against this background, the following problems are posed: providing a coating material for HMC process and a dispersion material coated with a coating that does not have the drawbacks of the prior art discussed previously; and to provide an HMC process that is also suitable for coating a dispersed material having one or more pharmaceutically active ingredients with a composition of a coating material that desirably does not have separation of the mixture before or after coating the used composition, and does not exhibit any variation changes that occur with changes in coating volume due to polymorphism. Furthermore, if desired, the coating material ensures stable release kinetics and in doing so can also be processed, if desired, with dispersed materials having a thermally unstable pharmaceutically active ingredient. A pharmaceutically active ingredient is herein understood to mean a substance which can be used as a pharmacologically active component of a medicament. Substances here are chemical elements and chemical compounds and naturally occurring mixtures and solutions thereof, plants, parts of plants, plant components, algae, fungi and lichens in the treated or untreated state, animal bodies in the treated or untreated state, also living animals and body parts, body components and metabolites of humans or animals, and microorganisms including viruses and components or metabolites thereof. Here, the medicament is the following substance or a preparation made of the following substance: the substances are intended for use in or on the human or animal body and are intended as medicaments having properties for curing or alleviating or for preventing diseases or pathological conditions in humans or animals, or can be used in or on the human or animal body or administered to humans or animals in order to restore, correct or influence physiological functions by pharmacological, immunological or metabolic effects or for medical diagnosis. Also considered herein as medicaments are: articles comprising a medicament in the above sense or articles to which a medicament in the above sense is applied and articles intended to be in permanent or temporary contact with the human or animal body, and also substances and preparations of substances which interact with other substances or preparations of substances, intended for indicating the composition, status or function of an animal body or for revealing pathogens in animals without the need for use on or in the animal body.

The above-mentioned problems are solved by a coating material according to claim 1, a dispersion material according to claim 14 and a combination of such coating materials and a hot-melt coating method according to claim 17, wherein advantageous embodiment variants are given by the respective dependent claims.

A coating material for use in a hot-melt coating method is proposed, which comprises as a main component one or more polyglyceryl fatty acid esters, each obtained by the complete or partial esterification of a linear or branched polyglyceryl containing two to eight glyceryl units with one or more fatty acids, each fatty acid containing 6 to 22 carbon atoms. The main component here means the highest percentage of polyglycerol fatty acid ester by weight of the proposed coating material. The proposed coating materials preferably consist of polyglycerol fatty acid esters or post-synthesis mixtures of these polyglycerol fatty acid esters, with the exception of accompanying substances which can account for up to 2% by weight in connection with the synthesis.

The simplest polyglycerol that can be used as a starting material for the desired esterification is of empirical formula C₆Linear and branched diglycerol of O5H14, provided synthetically in a manner known in the industry, for example by reacting glycerol with 2, 3-epoxy-1-propanol and forming ether bonds under base catalysis, or by thermal condensation under base catalysis, wherein the isolate comprising mainly diglycerol can subsequently be isolated.

Diglycerol can exist in three different structurally isomeric forms, namely, a linear form in which an ether bridge is formed between the respective first carbon atoms of the two glycerol molecules employed, a branched form in which an ether bridge is formed between the first carbon atoms of the first glycerol molecules employed and the second carbon atoms of the second glycerol molecules employed, and a nuclear-dendritic form in which an ether bridge is formed between the respective second carbon atoms. In the case of base-catalyzed condensation of two glycerol molecules, up to about 80% is present in the linear form and up to about 20% in the branched form, while only a very small amount of the nuclear dendritic form is produced.

Likewise, to perform the desired esterification with fatty acids, polyglycerols comprising more than two, up to eight glyceryl units may be used. Typically, polyglycerol is abbreviated to "PG" and provided with an integer n as a subscript, the integer n providing the number of polyglyceryl units and thus being "PG"_n". For example, triglycerides may be represented as PG₃And may have empirical formula C₉O₇H₂₀. Now available as PG_nComplete esterification with fatty acids (e.g. stearic acid) occurs at all free hydroxyl groups of the molecule and thus, in the case of linear PG3, occurs at the first and second carbon atoms of the first glyceryl unit, at the second carbon atom of the second glyceryl unit and at the second and third carbon atoms of the third glyceryl unit. Thus, the empirical formula for this example may be represented as C9O7H15R5, where each R may represent a fatty acid residue, theThe empirical formula of the fatty acid residue in selected examples is C₁₈OH₃₅。

However, for the abbreviation of polyglycerols esterified with saturated unbranched fatty acids, the name pg (n) -Cm full ester or, where applicable, pg (n) -Cm partial ester has been established, wherein "n" in parentheses indicates the number of glyceryl units contained in the molecule in a similar manner to the name of polyglycerols, and m represents the number of carbon atoms of saturated fatty acids used for the esterification reaction. Thus, n represents the number of glyceryl units of empirical formula C3O2H5R, or correspondingly C3O3H5R2 for the marginal glyceryl units, wherein R may represent a fatty acid residue or a hydrogen atom of a free hydroxyl group. Thus, the PG (2) -C18 full ester will refer to the polyglycerol fatty acid full ester having an empirical formula of C78O9H 150. In the case of PG-partial esters, the number of fatty acid residues is averaged, with the empirical formula simultaneously indicating the isolate with the most esterified variant present. A more precise name for a polyglycerol fatty acid partial ester is provided by an additional representation of the hydroxyl number, which is a measure of the unesterified hydroxyl content, and thus provides information about the degree of esterification of the partial ester. In this case, it may be preferable for steric reasons to carry out the esterification reaction from the outside to the inside. Thus, those hydroxyl groups which allow the fatty acid residue to have the highest degree of freedom are esterified first. Thus, the first esterification reaction on the linear polyglyceryl units preferably occurs at the hydroxyl group of the first carbon atom of the edge polyglyceryl unit, and then the second esterification reaction occurs at the hydroxyl group of the third carbon atom at the other end of the edge polyglyceryl unit. Next, the hydroxyl group at the carbon position immediately adjacent to the position that has been esterified is esterified, and so on.

Fatty acids are understood here to mean aliphatic monocarboxylic acids containing from 6 to 22 carbon atoms, which are preferably unbranched and saturated and have an even number of carbon atoms, but which may also be odd-numbered, branched and/or unsaturated. Particularly preferably, for the preparation of the proposed polyglycerol fatty acid esters, unbranched saturated fatty acids containing 16, 18, 20 or 22C atoms are used, thus palmitic acid, stearic acid, arachidic acid or behenic acid are used.

Surprisingly, the proposed polyglycerol fatty acid esters show no polymorphism, in contrast to monoglycerol fatty acid esters (like e.g. triacylglycerols). The polyglycerin fatty acid esters, each detected separately using dynamic differential calorimetry (dynamische diffrenzkalorimetrie), had only endothermic minima on heat flow (expressed in mW/g) during heating, which occurred due to melting of the detected sample, and only exothermic maxima during cooling, which occurred due to solidification of the detected sample. In contrast, in the detection of triacylglycerols with polymorphisms, different local minima were found, i.e. a first local endothermic minimum when the α -modification melts when the sample is heated, followed by a local exothermic maximum during crystallization to the more stable β -modification, which is indicated by another local endothermic minimum of heat flow to also melt with further increase in temperature. The temperature during heating and during cooling varies uniformly with time. No additional endothermic or exothermic transition was observed during storage at ambient or 40 ℃ for 6 months.

The individual detection of the proposed polyglycerol fatty acid esters with Wide Angle X-ray Scattering (abbreviated as "WAXS") below their respective coagulation temperature shows a maximum peak in intensity of all the detected polyglycerol fatty acid esters, which peak in intensity gives a deflection Angle of correspondingly 21.4 ° which corresponds to about 2q, i.e. to twice the bragg Angle, resulting in a spacing of the network planes of 415pm, which here is related to the layer stacking density of the detected molecules. This distance can be structurally assigned to the α -variant in which the respective layer structures are arranged parallel to one another in a hexagonal lattice with molecules stacked one on top of the other forming a plane. Other variants may not be identified. The stability of the identified alpha-variants was also observed using WAXS at both room temperature and 40 ℃ for 6 months, respectively. In this case, surprisingly stable α -variants were also found exclusively for the polyglycerol fatty acid esters tested.

The following further confirmation was obtained by a single analysis of the widest variety of polyglycerol fatty acid esters by Small Angle X-ray Scattering (abbreviated SAXS): the proposed polyglycerin fatty acid ester has no polymorphism. SAXS allows conclusions to be drawn about the size, shape and inner surface of the crystallites. Here, the thickness of the corresponding crystallite can be calculated using the scherrer equation, according to which D ═ K λ/FWHM cos (θ) applies. D here denotes the thickness of the crystallites and K denotes a dimensionless so-called scherrer constant which allows the shape of the crystallites to be expressed and is usually taken to a very approximate value of 0.9. FWHM stands for "Full Width at Half Maximum" (i.e. for the Width of the peak of the Maximum intensity peak at Half height for the condition measured in radians (rad) and theta is the bragg angle, i.e. theta is the angle of incidence of the radiation into the plane of the network. The samples known from the prior art of tripalmitin stabilized with 10% polysorbate 65 had a crystallite thickness of 31nm (corresponding to 7 lamellae) after six months of storage at ambient temperature and the above-mentioned samples had a crystallite thickness of 52nm (corresponding to 12 lamellae) after six months of storage at 40 ℃, almost doubled, whereas the proposed partial polyglycerol fatty acid esters predominantly showed a crystallite thickness of 20 to 30nm (corresponding to 2 to 4 lamellae) and were stable in the unaltered variant after six months of storage at 40 ℃. In contrast, polyglycerol full esters mainly show slightly increased crystallite thicknesses of 30 to 40nm (corresponding to 5 to 8 lamellae) indicating a higher degree of organization and are likewise stable in the unaltered variant after six months of storage at 40 ℃.

The following polyglycerol fatty acid full esters are preferably used in or as HMC coating materials: PG (2) -C18, PG (2) -C22, PG (3) -C22, PG (4) -C16 and PG (4) -C16/C18 and PG (6) -C16/C18, respectively, with ratios of C16 and C18 complementary to each other to 100, which are 35 to 45 to 55 to 65, preferably 40 to 60. The full esters from this group have melting points below 80 ℃ and even below 60 ℃ in addition to PG (2) -C22 and PG (3) -C22, and are therefore very suitable for the HMC process, especially also because their decisive freezing points are approximately 3 ℃ to 7 ℃ below the respective melting points in this process. The above description also applies to the following partial polyglycerol fatty acid esters, where in the following, correspondingly preferred ranges of typical average hydroxyl values in first brackets and correspondingly particularly preferred typical average hydroxyl values in second brackets are added in the name: PG (2) -C22- [ 15-100 ] - [17], PG (3) -C22- [100-200] - [137], PG (4) -C16- [150-250] - [186], PG (4) -C18- [100-200] - [168], PG (4) -C22- [100-200] - [145], PG (6) -C18- [100-200] - [133] and PG (3) -C16/C18- [100-200] - [148], PG (4) -C16/C18- [150-250] - [187], PG (6) -C16/C18- [200-300] - [237], wherein the ratio of C16 to C18 is 40 to 60, respectively. The partial esters mentioned also have melting points below 80 ℃ and even below 60 ℃ in addition to the partial PG (2) -C22 ester, PG (3) -C22 ester and PG (4) -C22 ester, where, like the full esters, the freezing points are about 3 ℃ to 7 ℃ below the corresponding melting points.

In order to make the proposed polyglycerol fatty acid esters suitable for the HMC process, their viscosity should be less than 300 mPas, preferably less than 200 mPas and particularly preferably less than 100 mPas at 80 ℃ since for molten coating materialsTong (Chinese character of 'tong') Often timesThe atomizing nozzles used are too prone to clogging at higher viscosities. The melting temperature limit of 80 ℃ of the coating material may only be exceeded in special cases, since the process control temperature must be set too high for sensitive drug substances in general.

Preferably, those of the proposed polyglyceryl fatty acid esters which have a setting temperature below 75 ℃ (particularly preferably between 43 ℃ and 56 ℃) for the HMC process are used, since the lower process control temperatures which are possible thereby are already targeted for reasons of energy consumption, process reliability and greater selectivity with regard to the dispersion materials which can be used. The solidification temperature is defined herein as the temperature value at which the maximum of the highest exothermic peak of the heat flow occurs upon cooling during analysis of the sample by dynamic differential calorimetry.

For the selection of the proposed polyglycerol fatty acid ester suitable for the dispersion material to be coated, the hydrophobicity of the polyglycerol fatty acid ester is important, since this is linked to the wettability, like the water absorption capacity and the erosion behavior of the coating materialHas an effect on the kinetics of release of the coated dispersed material. The hydrophobicity was determined by determining the contact angle between the coating material in the solid, aggregated state and a drop of pure water. From young's equation, cos θ ═ y_Sv-γ_SL)/γ_LVWherein γ is_SLIs the interfacial tension, gamma, between the coating material and water_LVIs the surface tension of a water droplet, and gamma_SvIs the interfacial tension between the coating material and the ambient air. Theta is the contact angle. Therefore, the larger the contact angle θ, the larger the interfacial tension between the coating material and water, and the higher the hydrophobicity of the coating material detected. The contact angles of the proposed polyglycerol fatty acid esters are also related to the HLB values customary in pharmaceutical technology, which on a scale of 0 to 20 provide information on the ratio of lipophilic to hydrophilic molecular moieties, wherein the hydrophilic moiety increases with increasing HLB value. For the treatment of dispersed materials comprising one or more pharmaceutically active ingredients with the HMC method, the contact angle of the coated material under storage conditions should undergo only moderate changes, thereby ensuring stability of the release kinetics of the one or more active pharmaceutical ingredients. Therefore, it is preferable that those of the polyglycerin fatty acid esters whose contact angle has a deviation from the initial value of less than 10 ° after 16 weeks at 40 ℃ (likewise at 20 ℃) be used as the main component of the coating material. At 40 °, the deviation of the contact angle of glycerol tristearate under the mentioned conditions is relatively high and therefore does not favour the desired constancy of the release kinetics, for example due to a rearrangement from the α -variant to the β -variant during storage.

It is basically sufficient to provide the proposed coating material if the proposed coating material consists of polyglycerol fatty acid esters obtainable from esterification reactions, except for synthesis-related impurities (which are not more than 2% by weight), and all esterification reactions are carried out with the same reactants. However, for fine adjustment of the properties of the coating material, it is also possible to mix polyglycerol fatty acid esters, which are obtainable by esterification reactions that differ from one another due to different reactants, with one another after synthesis, as long as no separation occurs. Neutral dope mixing may also be performed to the polyglycerin fatty acid ester used for the coating material as long as the polyglycerin fatty acid ester is still the main component of the coating material, neither polymorphism nor separation occurs, stability of release kinetics exists, and melting and solidifying points of the mixture are below 80 ℃.

In order not to have an undesired separation process before or after the HMC process, preferably at least 98 wt.% of the coating material used in the HMC process consists of polyglycerol fatty acid esters.

In contrast to the already known coatings or coating agents, the proposed coating materials are preferably free of solvents which, after application of the dispersion material, have to be removed by evaporation in an energy-consuming and time-consuming drying step. The coating material is also advantageous without any surfactant additives, since in the case of such additives there is often the risk of undesired separations which are usually only manifested in long-term tests in connection with storage stability.

The use of the proposed coating material having the polyglycerin fatty acid ester as the main component is not limited to the HMC method, regardless of any method, as long as the coating material is changed into a hollow spherical heterogeneous isomorphous by spraying a melt of the coating materialThe hollow spherical heteroisomorphous shape has an internal cavity with the above-described dispersion material, wherein the dispersion material preferably has at least one active pharmaceutical ingredient. Surprisingly, it is also possible to coat the crystals of one or more active pharmaceutical ingredients with the proposed coating material in a stable manner without it being necessary to provide the particles or agglomerates with one or more adjuvants beforehand.

Hot-melt coating processes, in which a dispersion material is coated with a coating material having a composition according to one of claims 1 to 13, leads to superior end products compared to the prior art, which can be well regulated in terms of their release kinetics and can also be stored for longer periods without a reduction in quality. Thus, such hot melt coating process is expected to also provide a melt coating to a dispersed material having at least one pharmaceutically active ingredient, in particular also to provide such a dispersed material having at least one thermally unstable pharmaceutically active ingredient, wherein thermally unstable here means that the effective activity has decreased by 2% after having been exposed for one hour at more than 100 ℃. When all molecules of the pharmaceutically active ingredient are present in their active form or can be converted in vivo to the active form, 100% of the effective activity of the pharmaceutically active ingredient is present.

Surprisingly, in the variation of the parameters of the HMC process that are critical to the results, in particular the air inlet temperature, it can be determined that for the proposed coating material the air inlet temperature does not have to be 5 ℃ to 15 ℃ lower than the solidification temperature of the coating material, but instead, can be increased by up to 1 ℃ to 2 ℃ due to the lower, specific heat capacity of the proposed coating material compared to the prior art, and thus effectively prevent the formation of undesired agglomerates during the spraying process.

Detailed Description

In the following, the properties of the proposed coating material and the combination of coating material and dispersing material, and in what way which parameters are considered in a hot-melt coating method using the proposed coating material, are explained in more detail using illustrations and examples.

595g of PG are added₄And 625g of C18 fatty acid were placed in a glass apparatus with a distillation bridge and melted. The reaction is carried out under vacuum at 200 ℃ to 240 ℃. Esterification is carried out until AN is reached<1.0mg KOH/g.

The partial ester PG (4) -C18 synthesized as described above showed the quantitative main structure shown in FIG. 1 when examined by gas chromatography-mass spectrometry (GC-MS).

Fig. 2 shows the results of the detection of PG (4) -C18 using dynamic differential calorimetry, wherein the temperature values on the X-axis of the graph are assigned to the heat flows in mW/g on the Y-axis. The diagram on the left of FIG. 2 shows two almost congruent curves of two measurements of the partial ester PG (4) -C18, each of which has exactly one endothermic minimumThe endothermic minimum can be assigned to the energy-consuming transition from the solid phase to the liquid phase upon melting of the partial ester. The diagram on the right of fig. 2 shows exactly one exotherm maximum of the partial ester PG (4) -C18, which can be assigned to the energy-releasing transition from the liquid phase to the solid phase upon solidification of the partial ester. Using NietzschMeasurements were performed by DSC 204F1 Phoenix, from GmbH,95100Selb, Germany. Therein, 3-4 mg of sample was weighed into an aluminum crucible and the heat flow was continuously recorded at a heating rate of 5K per minute. The second round was performed at the same heating rate.

Figure 3 shows typical performance of polymorphic triacylglycerols during detection using dynamic differential calorimetry when heated compared to the expected performance of polyglycerol fatty acid esters. Here, two local endothermic minima with an exothermic maximum between them can be seen, the first endothermic minimum on the left occurring as a result of the melting of the unstable α -modification, followed by an exothermic maximum upon crystallization to the more stable β -modification, which in turn melts upon a further increase in temperature, which can be identified by the second endothermic local minimum on the right.

Fig. 4 shows partial esters of PG (4) -C18 detected by dynamic differential calorimetry upon heating after 6 months of storage at ambient temperature. FIG. 5 shows partial esters of PG (4) -C18 detected by dynamic differential calorimetry upon heating after storage at 40 ℃ for 6 months. In both cases, there is still no visible maximum of the exotherm which could indicate crystallization to a more stable variant after melting.

For WAXS and SAXS analysis, a point focus camera system S3-MICRO (formerly Hecus X-ray Systems Gesmbh,8020Graz, Austria, now Bruker AXS GmbH,76187Karlsruhe, Germany) equipped with two linear position sensitive detectors with resolutions ranging from 3.3 angstroms to 4.9 angstroms (WAXS) and 10 angstroms to 1500 angstroms (SAXS) was used. The sample was introduced into a glass capillary of about 2mm diameter, which was subsequently sealed with wax and placed in a capillary rotation unit. A single measurement was exposed to an x-ray beam having a wavelength of 1.542 angstroms for 1300 seconds at ambient temperature.

Fig. 6 shows the results of the WAXS analysis below its solidification temperature for various polyglyceryl fatty acid esters including PG (4) -C18 partial ester (labeled), all showing a maximum in strength at 21.4 ° 2 θ. The bragg angle corresponds to the distance of the network plane of 415pm, which is typical for a layered stack of alpha-variants. The intensity maximum remained stable both when stored at ambient temperature for 6 months (as shown in FIG. 7) and when stored at 40 ℃ for 6 months (as shown in FIG. 8).

FIG. 9 shows the results of SAXS analysis of various partial polyglycerol fatty acid esters. The lamella distance of 65.2 angstroms can be deduced for the PG (4) -C18 partial ester. According to the scherrer equation, the thickness of the crystallites is 12.5nm with a scherrer constant of 0.9, a wavelength of 1.542 angstroms, a FWHM value of 0.0111 and a bragg angle θ of 0.047 (rad). The value of the SASX analysis of the PG (4) -C18 partial ester remained constant after six months of storage at ambient temperature and 40 ℃ (not shown).

Rheometer Physica-modular compact rheometer (MCR 300, Anton Paar GmbH,8054Graz, Austria) was used to measure viscosity. Measurements were performed on a CP-50-2 system with a conical plate using constant shear force. Here, the sample was melted directly on the plate, and the viscosity was determined at 80 ℃ and 100 ℃. The viscosity of the partial PG (4) -C18 esters was 74.38 mPas at 80 ℃ and 34.46 mPas at 100 ℃ respectively. Thus, the partial esters can be handled well in hot-melt coating processes.

Evaluation by dynamic differential calorimetry also allows the setting temperature of the PG (4) -C18 partial esters to be expressed. The peak of the exotherm maximum upon cooling of the sample occurred between 53.4 ℃ and 57.0 ℃ and the maximum was at 55.2 ℃, which is labeled as the solidification temperature.

Fig. 10 shows a graph illustrating the measurement of the contact angle (see paragraph [0020 ]). For the partial ester PG (4) -C18, the contact angle was about 84 °, which correlates to an HLB value of about 5.2. The PG (4) -C18 partial ester is assigned to a polyglycerol fatty acid ester with higher hydrophilicity than other polyglycerol fatty acid esters, as can be seen from fig. 11 (PG 4-C18 in the figure), and is therefore suitable for coating of active pharmaceutical ingredients where immediate release is desired, since the HLB value of 5.2 is above the HLB fast release limit of about 4. Fig. 12 shows the change in contact angle of the partial ester PG (4) -C18 (middle panel) compared to the initial measurement (left column) after 16 weeks at ambient temperature (middle column) and after 16 weeks at 40 ℃ (right column). The change in contact angle does not exceed 10 deg., and thus hydrophobicity can be described as stable compared to monoglycerol fatty acid esters (such as, for example, tristearyl glycerol). The above description also applies to the partial esters PG3-C16/C18 (left panel) and PG6-C18 (right panel) as shown in FIG. 12.

Figure 13 shows the release kinetics of particles coated with the partial ester PG (4) -C18, each partial ester having 600mg of N-acetylcysteine, and alternatively with the partial ester PG (3) -C16/C18. The content of partial PG (4) -C18 ester was 45% by weight and PG (3) -C16/C18 ester was 50% by weight, based on the total weight of the coated particles. The values on the Y-axis represent the percentage content of N-acetylcysteine released and the values on the X-axis represent the time in minutes. The release studies were performed using a USP-II compliant apparatus DT820LH (ERWEKA GmbH,63150Heusenstamm, Germany) with an automated sample collector. The collected samples were analyzed by High Pressure Liquid Chromatography (HPLC) under the following conditions: column: synergi Fusio RP4mm, 80 angstroms, 250 mm. times.4.6 mm; an upstream column: atlantis T3(5 μm); mobile phase: acetonitrile 5%/water 95% (pH 1.6); flow rate: 1 mL/min; sample introduction amount: 20 mm; column temperature: 21 ℃; temperature of the automatic sample collector: 5 ℃; wavelength: 220 nm; operating time: for 20 minutes. The particles coated with partial ester of PG (4) -C18 had an immediate release profile, in which less than 10% of the N-acetylcysteine was released in the first 5 minutes and more than 85% of the N-acetylcysteine was released in the first 30 minutes. To achieve more effective taste masking, the HMC process used can also be carried out with higher temperature of the incoming air used and higher spray rate in order to further reduce the release of N-acetylcysteine in the first 5 minutes. Taste masking may be considered successful due to the release kinetics of particles coated with PG (3) -C16/C18 partial esters. Here, little release occurs within the first 5 minutes, which is critical for taste masking.

Figure 14 shows the release kinetics of N-acetylcysteine particles coated with partial ester of PG (4) -C18 initially, after one month, three months, and five months of storage at 40 ℃. The release kinetics are not obviously different, and the product is stable.

Figure 15 shows the release kinetics of N-acetylcysteine particles coated with partial ester of PG (3) -C16/C18 initially, after one month of storage at ambient temperature and after one month of storage at 40 ℃. The release kinetics are also not significantly different here.

Successful taste masking using coating materials with PG (3) -C16/C18 partial esters as the main component can be achieved not only by optimization of the HMC process parameters. The Innojet Ventilus V-2.5/1 laboratory system was used as a coating device in combination with an Innojet thermofusion device IHD-1(Romaco Holding GmbH,76227Karlsruhe, Germany). The partial ester PG (3) -C16/C18 was melted at 100 ℃ and sprayed onto N-acetylcysteine crystals having an average diameter of about 500 μm. The sample sizes for the HMC runs were 200g of dispersed material, respectively. The spray rate and air inlet temperature were varied in various HMC runs to determine the optimum settings for coating. Wherein the effectiveness of the coating method is determined according to the following equation: the effectiveness (%) — the actual coating amount per theoretically achievable coating amount x 100, wherein the actual coating amount is the percentage content of coating material applied to the acetylcysteine crystals used in the corresponding HMC run. At a spray rate of 5g/min and an air inlet temperature of 35.0 ℃, the effectiveness was 90.7%. Increasing the air inlet temperature to 40.0 ℃ increased the effectiveness to 91.0%. Surprisingly, an increase in spray rate to 7.5g/min and an increase in air inlet temperature to 50 ℃ resulted in 100% effectiveness. The two effectiveness values of 90.7% and 91.0% mean that 9.3% by weight or respectively 9.0% by weight of the coating material solidifies before diffusion and distribution can take place on the surface of the N-acetylcysteine crystals. The solidified droplets without active ingredient were collected as dust at the end of the respective run and weighed. At 90.7% effectiveness, the dust was 18.6g, and at 91.0% effectiveness, the dust was 18.0 g. Wherein 100% effectiveness is achieved at an air inlet temperature 2 ℃ lower than the solidification temperature of the coating material (in this case PG (3) -C16/C18 partial ester, which has a solidification temperature of 51.7 ℃). The low specific heat capacity of the polyglycerol fatty acid esters used for the proposed coating materials compared to conventional HMC coatings may be the reason for the advantageous flexibility in the setting of the air inlet temperature which is now possible compared to the prior art. In the publication "Solvent-free recording technologies for the preparation of lipid-based solid objects" (Pharmaceutical Research, 5.2015, 32(5), 1519-45) by K.Becker et al, an air inlet temperature of 5 ℃ to 15 ℃ below the solidification temperature of the HMC coating material is still considered essential.

In contrast to the release test with the coating material having the partial ester PG (4) -C18, in order to determine the release kinetics of N-acetylcysteine crystals coated with the partial ester PG (3) -C16/C18, an integrated UV radiation/visible light detection was performed using a Lambda 25 spectrometer (Perkin Elmer inc., Waltham, Massachusetts, USA) instead of an automatic sample collector. The release test was carried out in 900mL of ultrapure water from Merck KGaA, Darmstadt, Germany at 37 ℃ with a paddle stirring speed of 100 revolutions per minute. The release characteristics are scaled as: initially set at 0% and at the end of release 100% of the release level was released. Fig. 16 shows the release profiles of the coated particles at air inlet temperatures of 35 ℃, 40 ℃ and 50 ℃ in the HMC process. The particles coated at 50 ℃ with 100% effectiveness released almost no N-acetylcysteine within the first 5 minutes. Thus, after optimization of the air inlet temperature, it is surprisingly possible in this way to make the HMC process using coating materials with PG (3) -C16/C18 partial ester as main component very suitable for taste masking in the case of the use of the proposed coating materials.