Sustained release preparation of a macrolide compound like tacrolimus

The This invention relates to a formulation for use on a medical field, which contains a macrolide compound and the with an extraordinary property good, delayed Release is provided.

A oral formulation of one of macrolide compounds, namely tacrolimus with a useful immunosuppressive Activity, was prepared as a solid dispersion composition, the rapid release property using polymers, such as hydroxypropyl methylcellulose, and a solubilizing agent (see, for example <patcit><text>EP 0240773</text></patcit>) owns. Due to the presence of the solubilizing agent is this Formulation, a formulation with fast release. by virtue of the high absorbability it is high in the clinical field assessed. Alternatively, was in clinical practice the occurrence of an oral Tacrolimus formulation with a sufficient long action and excellent oral absorbability expected. For one However, those skilled in the art that the absorbability a pharmaceutically active agent orally in the form of a Formulation having delayed Release is given, is generally reduced and / or that a non-negligible change the absorbability is observed. The inventors of the present Invention have conducted a series of studies. The Inventors have invented sustained-release formulations of macrolide compounds, wherein a representative thereof is tacrolimus. The formulations are characterized in that the macrolide awarded is absorbed orally and / or that variation of its absorbability is suppressed.

The This invention relates to a macrolide formulation delayed Release wherein the loosening carried the macrolide compound under sustained release.

It An object of the invention, a macrolide sustained release formulation provide, wherein the time (T63.2%) required for the dissolution of 63.2% of the maximum Amount of the macrolide compound is necessary, is 0.7 to 15 hours, such as measured according to Japanese Pharmacopoeia, 13th edition, Dissolution Test, No. 2 (paddle method, 50 rpm) using a test solution containing an aqueous 0.005% hydroxypropyl cellulose solution is, which was adjusted to a pH of 4.5.

It A further object of the invention a solid dispersion composition provide a macrolide compound, which for the above-mentioned formulation sustained is usable release, wherein the macrolide compound in a amorphous state on a solid basis exists.

Of the T 63.2% value, which according to the invention with the dissolution test is determined, can be determined from the release curve created by plotting test data on graph paper becomes. However, the release profile of a drug can in Generally by adjusting the data of the dissolution test on a model release are analyzed, and such a method may also be in the calculation the T63.2% value is used. The model for the adaptation, which uses may be, includes the first-order model or a linear Model, a model of zero order, a cube root model, etc., as described in Yamaoka, K. &amp; Yagahara, Y .; Introduction to Pharmacokinetics gave a microcomputer, Nankodo, 138. As a model, with all Kinds of release patterns with the highest validity can be shown, known Weibull function, described in the above book is in and LJ Leeson &amp; J. T. Carstensen (ed.): Release of Pharmaceutical Products (American Pharmaceutical Society) (Chizin Shokan), pp 192-195.

The Weibull function is a function with which the dissolution rate (%) With time (T) can be expressed by the following equation can; <st32:df xmlns:st32="http://lighthouseip.com/">dissolution rate (%) = D<st32:sub>Max</st32:sub> × (1 - exp [- ((T - Ti)<st32:sup>n</st32:sup>) / M]),</st32:df>wherein D_Max the maximum dissolution rate at infinite time , m is a scale parameter, the dissolution rate of the , n is a shape parameter which the shape of the dissolution curve represents, Ti is a position parameter, the deceleration phase the until the start of the dissolution represents. The resolution characteristic a pharmaceutical product can be accomplished using this parameter expressed in combination will.

Around the data of the dissolution test adapt to the Weibull function, and the corresponding parameters to calculate the non-linear method of least squares used which is described in &lt;?page 3?&gt;Yamaoka, K. &amp; Yagahara, Y .; Introduction to Pharmacokinetics with a Microcomputer, Nankodo, p.40, mentioned above. The Parameters are determined at a time point where the sum of the squares the differences between the values ​​represented by the above equation are calculated and the measured values ​​at each time point minimal is. The dissolution curve, which using these parameters with the above equation is calculated, is the curve that most accurately measured Values ​​represented.

The Meaning of each parameter of Weibull function is now explained.

D_Max (Maximum dissolution rate) is the maximum dissolution rate at infinite time, as mentioned above, generally the Value of D_Max preferably as close as possible to 100 (%) is.

m (Scale parameter) is a parameter of the dissolution rate is a pharmaceutical product. The smaller the value is of m is, the larger the dissolution rate and similarly Example, the larger the Value of m is, the lower is the dissolution velocity.

n (Shape parameter) is a parameter representing the shape of a dissolution curve represents. If the value of n is 1, the Weibull function as dissolution rate (%) = D_Max × (1 - exp [- (T - Ti) / m]) are written. There this is equivalent is a first-order kinetics, the dissolution curve linear. If the value of n is less than 1, is the dissolution curve a plateau. If the value of n is greater than 1, there is a sigmoid dissolution curve in front.

Ti (Position parameter) is a parameter, the delay phase, representing up to the start of the resolution.

The Macrolide formulation having delayed Release according to the present Invention can be characterized by means of Weibull function will. The task-related formulation The sustained-release can thus be realized by D_Max (maximum Dissolution rate) to 80% or more is set, preferably on 90% or more, wherein 95% or more even more are preferred, is set m (scale parameter) at 0.7 to 20, preferably 1-12, wherein 1.5-8 more preferably, n (shape parameter) is set to 0.2-5, preferably to 0.3-3, wherein 0.5-1.5 more is preferred, and Ti (position parameter) is set to 0-12 is, preferably 0-8, wherein 0-4 is more preferable.

Of the Value obtained by substituting the parameter values ​​of m and n from the above Weibull function into the term m^{1 / n} found is, represents the time in which 63.2% of the maximum amount of dissolution of the active ingredient from the formulation (T63.2%) is released. This means T63.2% (hr) = m^{1 / n}, The Release characteristic of the sustained-release formulation according to the invention can with the dissolution test, Method 2 (Paddle method, 50 rpm) of JP XIII are evaluated using a test solution is used, a aqueous, 0.005% solution is hydroxypropyl cellulose, the adjusted to a pH of 4.5 is. In the macrolide sustained release formulation according to the present invention, the time (T63.2%) in which 63.2% of the maximum amount of macrolide compound to be dissolved is released from the formulation, from 0.7 to 15 hours. In the past A rapid-release formulation with a macrolide already made, but as yet no formulations sustained Release were prepared, wherein 0.7 to 15 hours 63.2% T is and for clinical practice useful would. The present invention provides this for the first time. If the T 63.2% value is shorter than 0.7 hours, the efficacy of the macrolide compound are not sufficiently delayed after oral administration. When the formulation a T 63.2% value has more than 15 hours, the release of the active ingredient is so delayed be that the drug from the body is eliminated before an effective blood concentration is reached. This would be for a formulation according to the invention not suitable. When T63.2% is 1.0-12 hours, can favorable delayed Release can be achieved. More preferably T is 63.2% value from 1.3 to 8.2 Hours, most preferably a sustained release formulation is where the T 63.2% value 2-5 is hours.

Of the Term "macrolide compound" for use according to the invention is a generic name of compounds with 12 members or more, which belong to the lactones with a large ring. Numerous Macrolide compounds, which, of microorganisms of the species Streptomyces such as rapamycin, tacrolimus (FK506) and ascomycin, and the analogs and the derivatives thereof are within the term macrolide compound includes.

The Macrolide compound according to the invention is a tricyclic compound having the following formula (I). &lt;?page 4?&gt;<img img-content="cf" img-format="tif" he="87" wi="98" file="00060001.tif" />wherein the adjacent pairs of R¹ and R², R³ and R⁴ and R⁵ and R⁶ each independently from one another <ul><li>(A) two adjacent hydrogen atoms are, but R² also an alkyl group may be, or</li><li>(B) may form another bond formed between the carbon atoms, with which they are associated, formed;</li></ul>R⁷ is a hydrogen atom, a hydroxy group, a protected Hydroxy group or an alkoxy group or an oxo group together with R¹; R^8th and R⁹ are independently a hydrogen atom or a hydroxy group; R¹⁰ is a Hydrogen atom, an alkyl group, an alkyl group having a is substituted or more hydroxy groups, an alkenyl group, an alkenyl group which may be substituted with one or more hydroxyl groups , or an alkyl group substituted by an oxo group is; X is an oxo group, (a hydrogen atom and a hydroxy group), (A hydrogen atom and a hydrogen atom) or a group which is represented by the formula -CH₂O -; Y is an oxo group, (a hydrogen atom and a hydroxy group), (A hydrogen atom and a hydrogen atom) or a group which is represented by the formula N-NR¹¹R¹² or N-OR¹³; R¹¹ and R¹² are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²² and R²³ are independently a hydrogen atom or an alkyl group; R²⁴ is a optionally substituted ring system containing one or more hetero atoms may contain; n is an integer of 1 or 2; and in addition to the above definitions, Y, R¹⁰ and R²³. together with the carbon atoms to which they are connected, a saturated or unsaturated, 5- or 6-membered nitrogen, sulfur and / or oxygen-containing, represent heterocyclic ring, which is optionally substituted with one or more groups that are selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a Benzyl, a group of formula -CH₂Se (C₆H₅) And an alkyl, which is substituted with one or more hydroxy groups.

R²⁴ , a cyclo (C_5-7) be alkyl group which is represented by the following groups, <ul><li>(A) a 3,4-Dioxocyclohexylgruppe;</li><li>(B) a 3-R²⁰-4-R²¹cyclohexyl, in the R²⁰ Hydroxy, an alkoxy group, an oxo group or a -OCH₂OCH₂CH₂OCH₃-Group is and R²¹ is hydroxy, --OCN, a Alkoxy group, a heteroaryloxy which with suitable substituents may be substituted, a -OCH₂OCH₂CH₂OCH₃-Group, a protected Hydroxy, chlorine, bromine, iodine, Aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy or R²⁵R²⁶CHCOO- wherein R²⁵ on optionally protected Hydroxy or protected Amino, and R²⁶ is hydrogen or Methyl, or &lt;?page 5?&gt;R²⁰ and R²¹ form together are an oxygen atom in an epoxide ring; or</li><li>(C) a cyclopentyl group which is substituted by methoxymethyl, optionally protected Hydroxymethyl, acyloxymethyl (in which the acyl group optional Dimethylamino group which may be quaternized, or a carboxy contains, can be esterified), one or more amino and / or hydroxy groups, the protected could be, or Aminooxalyloxymethyl. A preferred example is a 2-Formylcyclopentylgruppe.</li></ul>

The in the above general formula (I) used and definitions the specific and preferred examples thereof are now explained and be defined in detail.

Of the Term "lower" means, as far as is otherwise indicated, a group having 1 to 6 carbon atoms.

Preferred examples for the "alkyl groups" and an alkyl moiety the "alkoxy group" include a straight or branched, aliphatic hydrocarbon radical, for example a lower alkyl group such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, pentyl, neopentyl and hexyl.

Preferred examples for the "alkenyl groups" include a straight or branched, aliphatic hydrocarbon radical having one Double bond, for example, a lower alkenyl group such as vinyl, propenyl (Z. B. allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.

Preferred examples for the "aryl groups" include phenyl, Tolyl, xylyl, cumenyl, mesityl and naphthyl.

Preferred Protective groups in the "protected hydroxy groups" and the protected amino are 1- (lower alkylthio) - (lower) alkyl group such as a lower Alkylthiomethyl (z. B. methylthiomethyl, ethylthiomethyl, Propylthiomethyl, isopropylthiomethyl, butylthiomethyl, Isobutylthiomethyl, Hexylthiomethyl, etc.), a C₁-C₄ alkylthiomethyl more preferred, and most preferably a methylthiomethyl group is; a trisubstituted silyl group such as a tri (lower) alkylsilyl (Eg. Trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyldiarylsilyl (eg. B. Methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl, etc.), a tri (C₁-C₄) alkylsilyl and C₁-C₄ Alkyldiphenylsilylgruppe more are preferred, with a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl being most preferred, and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group with substituted aromatic group or a carboxylic acid, sulfonic acid carbamate descended.

Examples for the aliphatic acyl groups include a lower alkanoyl group, the optional one or more suitable substituent has as Carboxy, eg. Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, Isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, Carboxybutyryl, Carboxyhexanoyl, etc .; a cyclo (lower) alkoxy (Lower) alkanoyl group optionally one or more suitable Substituent has as lower alkyl, z. B. cyclopropyloxyacetyl, Cyclobutyloxypropionyl, Cycloheptyloxybutyryl, menthyloxyacetyl, Menthyloxypropionyl, Menthyloxybutyryl, Menthyloxypentanoyl, Menthyloxyhexanoyl, etc .; a Camphorsulfonylgruppe or a lower alkylcarbamoyl group, the one or more suitable substituents, like carboxy or protected Carboxy, z. B. carboxy (lower) alkylcarbamoyl (z. B. carboxymethylcarbamoyl, Carboxyethylcarbamoyl, Carboxypropylcarbamoyl, Carboxybutylcarbamoyl, carboxypentylcarbamoyl, Carboxyhexylcarbamoyl, etc.), tri (lower) alkylsilyl (lower) alkoxycarbonyl (lower) alkylcarbamoyl (z. B. Trimethylsilylmethoxycarbonylethylcarbamoyl, Trimethylsilylethoxycarbonylpropyl-carbamoyl, Triethylsilylethoxycarbonylpropylcarbamoyl, tert-Butyldimethylsilylethoxycarbonylpropylcarbamoyl, Trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.

Examples for the aromatic acyl groups include an aroyl group, the optional one or more suitable substituents, like nitro, z. B. Benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, Nitronaphthoyl, etc .; and a arenesulfonyl, the optional one or more suitable substituent has, for. example, benzenesulfonyl, Toluenesulfonyl, Xylensulfonyl, naphthalenesulfonyl, Fluorbenzensulfonyl, Chlorbenzensulfonyl, Brombenzensulfonyl, Iodbenzensulfonyl, etc.

Examples for the aliphatic acyl groups substituted by an aromatic group are include an ar (lower) alkanoyl optionally a or more suitable substituents, like lower alkoxy or Trihalo (lower) alkyl, eg. Phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenyla&lt;?page 6?&gt;cetyl, etc.

More preferred acyl groups among the acyl groups mentioned above are a C₁-C₄ alkanoyl, the optional carboxy has, cyclo (C₅-C₆) Alkoxy (C₁-C₄) Alkanoyl group having two (C₁-C₄) Alkyls at the cycloalkyl moiety, Camphorsulfonylgruppe,₁-C₄) alkylcarbamoyl group, tri (C₁-C₄) alkylsilyl (C₁-C₄) alkoxycarbonyl (C₁-C₄) Alkylcarbamoyl group, benzoyl group, optionally comprising one or two has nitro groups, Benzensulfonylgruppe with halogen, or a phenyl (C₁-C₄) alkonoylgruppe with C₁-C₄ alkoxy and trihalo (C₁-C₄) Alkyl group. Among these, most preferred are acetyl, carboxypropionyl, Menthyloxyacetyl, Camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, Iodbenzensulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.

Preferred examples for the "5- or 6-membered, Nitrogen, sulfur and / or oxygen containing heterocyclic Ring "include a Pyrrolyl and tetrahydrofuryl.

"A heteroaryl which may be substituted by suitable substituents "moiety of" heteroaryloxy, which may be substituted with suitable substituents "may be a component be shown for R¹ the compound of the formula of EP-A-532.088, whereby preference is given to 1-Hydroxyethylindol-5-yl. This publication is hereby incorporated by reference.

The tricyclic compounds (I) and the pharmaceutically acceptable Salts thereof, for use according to the invention are in terms of their good immunosuppressive activity, their antimicrobial activity and other pharmacological activities well known and as such of value for the treatment or prevention of rejection reactions in transplantation of organs or tissues, graft-versus-host disease, autoimmune diseases and infectious diseases [EP-A-0184162, EP-A-0323042, EP-A-423 714, EP-A-427 680, EP-A-465 426, EP-A-480 623, EP-A-532 088, EP-A-532 089, EP-A-569 337, EP-A-626 385, WO 89/05303, WO 93/05058, WO 96/31514, WO 91/13889, WO 91/19495, WO 93/5059, etc.].

Especially are the compounds which are designated as FR900506 (= FK506), FR900520 (ascomycin), FR900523 and FR900525, products of microorganisms the species Streptomyces be prepared as Streptomyces tsukubaensis No. 9993 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (previously Fementation Research Institute Agency of Industrial Science and Technology) 1-3, Higashi 1-chome, Tsukubashi, Ibaraki, Japan, date of deposit October 5 1984 accession number FERM BP-927] or Streptomyces hygroscopicus subsp. Yakushimaensis Nr. 7238 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology), 1-3, Higashi 1-chome, Tsukubashi, Ibaraki, Japan, date of deposit January 12, 1985, accession number FERM BP-928] [EP-A-0184162]. FK506 (general name: tacrolimus) of the following chemical Structure is in particular a representative compound.

<img img-content="cf" img-format="tif" he="57" wi="79" file="00120001.tif" />

Chemistry Name: 17-allyl-1,14-dihydroxy-12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4-azatricyclo [22.3.1.0^4.9] Octacos-18-ene-2,3,10,16-tetraone.

The Examples of preferred The tricyclic compounds (I) are those wherein each of the adjacent pairs of R³ and R⁴ or of R⁵ and R⁶ independently form another bond between the carbon atoms with which they are associated, formed; &lt;?page 7?&gt;R^8th and R²³ independently a hydrogen atom are; R⁹ a hydroxy group; R¹⁰ a methyl group, an ethyl group, a Propyl group or an allyl group; X (a hydrogen atom and a hydrogen atom) or an oxo group; Y is an oxo group is; each of R¹⁴, R¹⁵. R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²² a methyl group; R²⁴ a 3-R²⁰-4-R²¹cyclohexyl , wherein R²⁰ a hydroxy, an alkoxy group, an oxo group or a -OCH₂OCH₂CH₂OCH₃Group, and R²³ a hydroxy, -OCN, an alkoxy group, a heteroaryloxy which may be substituted with suitable substituents may be, a -OCH₂OCH₂CH₂OCH₃Group, a protected Hydroxy, chlorine, bromine, iodine, Aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy or R²⁵R²⁶CHCOO- in which R²⁵ on optionally protected Hydroxy or a protected Is amino, and R²⁶ Is hydrogen or methyl , or R²⁰ and R²¹ together form an oxygen atom in an epoxide ring; and n is an integer of 1 or second

The most preferably, the tricyclic compounds (I) in addition to FK506, Ascomycinderivate as a halogenated ascomycin (z. B. 33-epi-chloro-33-desoxyascomycin), which in <patcit><text>EP 427.680</text></patcit>, Example 66a, discloses is.

The tricyclic compounds (I) have a similar basic structure, the called, the tricyclic macrolide structure, and have at least a similar biological property (z. B. the immunosuppressive activity).

The tricyclic compounds (I) can present in salt form, which well-known, non-toxic and pharmaceutically includes acceptable salts such as a salt with inorganic or organic Bases, particularly an alkali metal salt such as a sodium salt and Potassium salt, an alkaline earth metal such as calcium salt and a Magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and a N-benzyl-N-methylamine salt.

Regarding of the according to the present Invention macrolide compound used should be noted that this as conformational isomers and one or more stereoisomers such as optical and geometrical isomers due to the asymmetric or can be carbon atoms and double bonds. Such conformational and isomers are also within the scope of macrolide compound of the present Invention comprises. The macrolide compounds can also exist as solvates, which are also encompassed within the scope of the present invention. Preferred solvates be a hydrate and an ethanolate.

The Formulation having delayed Release according to the present Invention is a formulation comprising a solid dispersion composition a comprising, wherein the macrolide compound in an amorphous state is present on a solid basis, which to a T63.2% value of 0.7 15 hours shows. The presence or absence of a diffraction peak, of having X-ray crystallography, thermal analysis, etc. is detected, whether or indicates whether not a macrolide compound in the amorphous state on a Solid base present in the solid dispersion composition is.

The pharmaceutically acceptable basis that the reluctance of macrolide is in an amorphous state in the layer and the at ambient temperature is present in a solid state. This basis is selected from Wax and water Polymers.

Specific examples for the wax include glycerin monostearate and sucrose fatty acid esters (for As mono-, di- or triesters of sucrose with moderate to high fat having 8 to 20 carbon atoms, eg. as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, linoleic acid, etc.). additional examples for the wax include polyglycerin fatty acid ester. Each polyglycerol fatty acid esters, including Monoesters, diesters or polyesters of polyglycerol with fatty acids, satisfactory. Specific examples of the polyglycerol fatty acid esters Tetraglycerinhexabehenat, Decaglycerinmonocaprylat, Triglycerindicaprylat, Triglycerindidecanoat, Tetraglycerinmonolaurat, Hexaglycerinmonolaurat, Decaglyceryl monolaurate, Tetraglycerinmonooleat, Hexaglycerinmonooleat, Decaglycerinmonooleat, Triglycerindioleat, Tetraglycerindioleat, Decaglycerinsesquioleat, Tetraglycerinpentaoleat, Hexaglycerinpentaoleat, Decaglycerindecaoleat, Heptaglycerinmonolinoleat, Triglycerindilinoleat, Tetraglycerindilinoleat, Hexaglycerindilinoleat, Diglycerinmonostearat, Tetraglycerol, Hexaglycerinmonostearat, decaglycerol monostearate, Tetraglycerintristearat, Hexaglycerintristearat, Hexaglycerinsesquistearat, Tetraglycerol pentastearate, Hexaglycerinpentastearat, Decaglycerindecastearat, Tetra&lt;?page 8?&gt;glyceryl monopalmitate, Hexaglycerinmonopalmitat, Decaglycerinmonopalmitat, Tetraglycerintripalmitat, Hexaglycerintripalmitat, Hexaglycerinsesquipalmitat, Tetraglycerinpentapalmitat, Hexaglycerinpentapalmitat and Decaglycerindecapalmitat. Preferred polyglycerol fatty acid esters include Tetraglycerinhexabehenat (z. B. Poem J-46B under a trade name, manufactured by Riken Vitamin Co., Ltd.), tetraglycerol pentastearate (Z. B. PS-310 under a trade name, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), tetraglycerol (z. B. MS-310 under a trade name, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), Hexaglycerinpentastearat (PS-500 under a trade name, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), Hexaglycerinsesquistearat (SS-500 under a Trade name, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), Decaglycerol monostearate and a mixture thereof. More preferred Waxes are glycerin monostearate and low-HLB sucrose fatty acid esters (Z. B. F-50, F-20 F-10, etc., manufactured by Daiichi Kogyo Seiyaku, Co., Ltd.).

The weight ratio of the macrolide compound and wax is preferably 1: 10 to 1: 100, more preferred 1: 40 to 1: 60, when the wax to Example Glycerol is. The weight ratio is preferably 1: 0.2 to 1: 20, more preferred 1: 0.5 to 1: 5, when the wax, for example, a sucrose fatty acid ester is, the weight ratio is preferably 1: 0.1 to 1: 100, with 1: 0.5 to 1: 50 more is preferred that the wax is a polyglycerol fatty acid ester is.

Preferred water-insoluble Polymers include for example ethylcellulose, methacrylate copolymers (Z. B. Eudragits such as Eudragit E, R, S, RS, LD, etc.). If the water-insoluble Polymer is ethylcellulose, a pharmaceutically acceptable Ethyl cellulose according to the present Invention are used. However, the preferred viscosity is from 3 to 110 cps, more preferred 6-49 cps, wherein 9 to 11 cps at Most preferred is when the viscosity of 5% ethylcellulose-toluene / ethanol (80/20) solution with a viscosity test is measured, which is described in USP 23, NF18. is preferred for example ETHOCELL (viscosity: 10) (trademark, Dow Chemical (US)).

The weight ratio the macrolide compound and the water-insoluble polymer is preferably 1: 0.01 to 1: 10, more preferably 1: 0.1 to 1: 5, wherein 1: 0.1 to 1: 1 is most preferred if the water insoluble polymer Ethylcellulose. A weight ratio of 1: 0.5 to 1: 5 is most preferred if the water insoluble polymer is a methacrylate copolymer is.

The Formulation having delayed Release according to the invention Further, a water-soluble base contain and this added base is preferably one of following water-soluble polymers:

polyvinylpyrrolidone (PVP), cellulose polymer (hydroxypropylmethylcellulose (HPMC), hydroxypropylmethyl cellulose phthalate, methyl cellulose (MC), carboxymethylcellulose sodium (CMC-Na), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), etc.), pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG) with an average molecular weight of 4,000 or more, gelatin, etc.

For the use the water-soluble Polymers added individually or in a mixture of two or more. A more preferred, water-soluble Base is cellulose polymer or PVP. The most preferred, water-soluble Base is HPMC, PVP or a combination thereof. Specifically, HPMC having a low viscosity an effect with the desirable delayed Release exercise. An aqueous 2% solution of this type of HPMC has a viscosity 1-4000 cps, preferably 1 to 50 cps, more preferably 1 to 15 cps, as measured at 20 ° C with a viscometer of Brookfield type, in particular HPMC 2910 having a viscosity 3 cps is preferred (TC-5E, EW, Shin-estu Chemical Co., Ltd.).

The weight ratio the macrolide compound to these water-soluble base is preferably 1: 0.05 to 1: 2, more preferably 1: 0.1 to 1: 1, 1: 0.2 to 1: 0.4 being most preferred.

at the preparation of the solid dispersion composition of the present Invention, the above water-insoluble base alone or in Combination with the water-soluble Base be used. Since the water-base essential than the Solid base is set according to the invention, a suitable solution Profile the solid dispersion composition can be achieved by a appropriate amount of water-soluble Base is added as a water-soluble polymer (eg. B. HPMC). If desired, can also contain components other than the solid base described above are added to prepare a solid dispersion composition, as suitable carriers, (Lactose, etc.), binders, coloring agents, sweeteners, Flavorings, diluents, Antioxidants (vitamin E, etc.) and lubricants (eg. B. Synthetic Aluminum silicate, magnesium stearate, calcium hydrogen phosphate, Calciumstea&lt;?page 9?&gt;advice, Talc, etc.).

In dependence on the type of solid base is the dissolution rate of the macrolide compound from the solid dispersion composition sometimes slow or the initial dissolution rate it must be raised sometimes. In this case, the dissolution rate the macrolide compound from the solid dispersion composition be adjusted by the solid dispersion composition suitable solubilizers (Z. B. Cross-carmelose sodium (CC-Na), carboxymethylcellulose calcium (CM-Ca), low substituted hydroxypropyl cellulose (L-HPC), starch sodium glycolate, micro-fine crystal cellulose, Cross-povidone, etc.) or suitable surface active agents (eg. As polyoxyethylene hardened castor oil, polyoxyl stearate 40, polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester (HLB is more than 10), etc. can be added).

The Particle size of the solid dispersion composition wherein the macrolide compound in an amorphous state in a Solid basis exists, is equal to or less than 500 microns. The composition has in particular a particle size which through a 350 .mu.m, more preferred 250 microns, can pass sieve.

The Solid dispersion composition of macrolide compound, the in the formulation having delayed Release according to the present Invention is present, can be prepared by the procedures described are <patcit><text>EP 0 240 773</text></patcit> and WO 91/19495 and the like. The method described below.

The Macrolide in an organic solvent (eg., Ethanol, Dichloromethane or an aqueous Mixture thereof, etc.) dissolved and then is added to an appropriate amount of a solid base. The scoring Mixture is sufficiently dissolved or suspended or she is allowed to swell. The mixture is then sufficiently kneaded together. After removal of the organic solvent of the mixture of the residue is dried and ground and is then size reduction subject, whereby a solid dispersion composition is prepared can be wherein the macrolide compound in an amorphous state is present in the solid base. During the kneading process, can if necessary, lubricants such as calcium hydrogen phosphate, excipients, such as lactose, and the like the mixture may be added.

The Formulation having delayed Release, comprising a macrolide compound according to the invention can be prepared using a finely divided powder the macrolide compound. The particle size control of the macrolide can by means of a mill apparatus accomplished be what a routine procedure in the pharmaceutical industry is, as a pin mill, Hammer mill, jet mill and a dry or wet ball mill, to name a few examples. The fine powder of the macrolide compound should have a distribution of particle diameter is within the range have from 0.1-50 microns, preferably 0.2-20 .mu.m, 0.5-10 microns, more preferably are, and / or an average particle diameter of 0.2-20 microns, preferably 0.5-10 .mu.m, 1-5 microns, more preferably are.

The Solid dispersion composition of macrolide compound, which is prepared by the above methods, can be used as such as a formulation with delayed Release may be used. Taking account of handleability after oral dosing, the composition is, however, more preferably as a formulation with delayed Release prepared in the form of a powder, fine powder, granule, Tablet or capsule, wherein routine formulation methods applied (such. as molding).

If desired, the formulation may be delayed Release by mixing the solid dispersion composition the macrolide compounds with, for example, diluents or lubricants (such as Sucrose, lactose, starch, crystalline cellulose, synthetic aluminum silicate, magnesium stearate, calcium stearate, Calcium hydrogen phosphate, and talc) and / or colorant, sweeteners Flavorings and solubilizers for routine applications getting produced. The resulting mixture is then thoroughly together mixed to achieve a sustained release formulation. The formulation having delayed Release or the solid dispersion composition of macrolide compound to the present invention may preliminarily dispersed in water or juice be to them as a liquid formulation take orally.

The effective dose of the macrolide compound varies depending on the type of compound, the patient's age, his illness, the severity of the disease and other factors. In ERAL&lt;?page 10?&gt;NEN the active ingredient at a dose of about 0.001 to 1000 mg is used, preferably with from 0.01 to 500 mg, with 0.1 to 100 mg per day of therapeutic treatment of a disease most preferred is. In general, the average single dose of about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg.

After oral administration constitutes Makrolidformulierung sustained release according to the present Invention characteristically the macrolide delayed release, so as to obtain the pharmaceutical activity over a long period remains. According to the invention the frequency of administration of pharmacologically active can Macrolide compound to be reduced. In particular, it is possible to containing a macrolide to provide pharmaceutical formulation which can only be administered once a day. Further, it is now possible, provide a pharmaceutical composition which is free of the risk of undesired Side effects, temporary effect very high concentrations are caused. This provides the Expression of pharmacological efficacy over a sufficiently extended Period safely.

The Formulation having delayed Release according to the present Invention is useful for the treatment and / or prevention of the following diseases and health states due the pharmacological activities, which possess these tricyclic macrolide compounds (I).

rejection by transplantation of organs or tissues such as heart, kidney, Liver, bone marrow, skin, cornea, lung, pancreas, small intestine, Extremity, Muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc .; Graft-versus-host reactions following bone marrow transplantation; Autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple Sclerosis, myasthenia gravis, type I diabetes, etc .; and infections which are caused by pathogenic microorganisms (eg. B. Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.); inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases (eg., psoriasis, atopic Dermatitis, contact dermatitis, Ekzematoidreaktion, dermatitis seborrheic, Lichen planus, pemphigus, blisters pemphigoid, epidermolysis bullosa, Urticaria, allergic facial edema, Vasculitis, erythema, dermal eosinophilia, lupus erythematosus, Acne and alopecia areata); Autoimmune diseases of the eye (eg. B. keratoconjunctivitis, vernal conjunctivitis, uveitis associated, with Behcet's disease, keratitis, herpetic keratitis, conical keratitis, conical Epitheldystrophie, Keratoleukom, ocular Premphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry Eye), Phlyktäne, Iridozyclitis, sarcoidosis, endocrine ophthalmopathy, etc.); reversible, obstructive airways diseases [asthma (z. B. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or persistent asthma (z. B. Late Asthma and airway hyperresponsiveness) Bronchitis, etc.]; Mucosal or vascular inflammations (z. B. gastric ulcer, ischemic or thrombotic vascular injury, ischemic Bowel disease, enteritis, necrotising enterocolitis, intestinal damage, associated with thermal burns, leukotriene B4-mediated diseases); Intestinal inflammations / allergies (Z. B. zöliakable Diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis); related foods, allergic Diseases away with symptomatic manifestations of the gastrointestinal tract (Z. B. migraine, Rhinitis and eczema); Kidney disease (eg. B. Intestitialnephritis, Goodpasture's syndrome, hemolytic uraemic syndrome and diabetic nephropathy); Nervous diseases (eg. As multiple Myositis, Guillain-Barre syndrome, Meniere's disease, multiple neuritis, Solitärneuritis, Stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and radiculopathy); cerebral ischemic Disease (z. B. head injury, bleeding in the brain (eg. B. Subarachnoidblutung, intracerebral hemorrhage, cerebral thrombosis, cerebral embolism, Cardiac arrest, stroke, transient ischemic attack (TIA), hypertensive Encephalopathy, cerebral infarction); endocrine diseases (. Eg Hyperthyroidism and Graves's disease); Blood disorders (eg. For example, pure red Blutzelloplasie, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic Purpura, hämolythische Autoimmune anemia, Agranulocytosis, pernicious Anemia, megaloblastic anemia and anerythroplasia); Bone diseases (eg osteoporosis.); respiratory diseases (Z. B. sarcoidosis, pulmonary fibrosis and idiopathic interstitial Pneumonia); &lt;?page 11?&gt;Skin diseases (eg. As dermatomyositis, leucoderma vulgaris, ichthyosis vulgaris, photosensitivity, and T-cell skin lymphoma); Circulatory diseases (. Eg arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and Myocardose); collagen diseases (Z. B. scleroderma, Wegener's Granuloma and Sjorgren's Syndrome); obesity; eosinophilic fasciitis; Periodontitis (Z. B. damage the gums, periodontal, alveolar bone or Substantia óssea Dentis); nephrotic syndrome (eg glomerulonephritis.); male Alopecia, alopecia senile; muscular dystrophy; pyoderma and Sezary syndrome; with chromosomal abnormalities associated diseases (. Eg Down's syndrome); Addison Disease; through active oxygen-mediated diseases [eg. B. organ injury (eg. As ischemic Circulatory disorders Institutions (eg. As heart, liver, kidney, digestive tract, etc.) connected, with storage, transplantation, or ischemic diseases (eg. as thrombosis, Myocardial infarction, etc.)); Intestinal diseases (eg. As endotoxin shock, pseudomembranous Ulcerative colitis and induced by drugs or radiation becomes); Kidney disease (eg. As ischemic acute renal insufficiency, chronic renal failure); Lung diseases (eg. B. toxicosis caused by pulmonary oxygen or drugs (eg. B. Paracort, bleomycin, etc.), lung cancer and Lungenemphysum); Eye diseases (eg. B. cataracts, haemochromatosis (siderosis bulbi), retinitis pigmentosa, senile plaques, Glaskörpervernarbung, eye burn through Alkalis); Dermatitis (z. B. erythema multiforme, linear immunoglobulin A bubble Santander Matose, Cement dermatitis); and other diseases (eg. as gingivitis, Periodontitis, sepsis, pancreatitis, and diseases caused by environmental pollution caused (z. B. air pollution), aging, carcinogen, Metastases of Karcinomen and Hypobaropathie); Diseases, which are caused by histamine release or leukotriene C4 release; restenosis coronary artery following angioplasty and obstruction of postoperative adhesions; Autoimmune diseases and inflammatory conditions (Z. B. primary mucosal edema, autoimmune atrophic autoimmune gastritis, premature menopause, male Sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, ophthalmia sympathica, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis, lupus erythematosus discoid, Autoimmunorchitis, arthritis (z. B. arthritis deformans) or polychondritis); HIV infection, AIDS; allergic conjunctivitis; hypertrophic cicatrix and keloid due to Trauma, burns or surgery.

have also The tricyclic macrolides liver stimulating activity and / or activities for stimulating hypertrophy and hyperplasia of hepatocytes. Thus, the pharmaceutical composition according to the present invention useful for the Increase the effect of a therapy and / or prophylaxis of liver diseases [E. B. immunogenic diseases (eg. As chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis or sclerosing Cholangitis), partial liver resection, acute liver necrosis (z. B. Necrosis caused by toxins, viral hepatitis, Shock or anoxia), hepatitis B, hepatitis non-A and the non-B Type, cirrhosis and liver failure (z. B. sudden hepatitis, late-onset Hepatitis and acute episode of liver failure (acute liver failure in chronic liver diseases))].

The present composition is also useful for the increase of the effect for the prevention and / or treatment of various diseases because of the useful pharmacological activity This tricyclic macrolides, such as reinforcing activity of a chemotherapeutic effect, activity of cytomegalovirus infection, antiinflammatory activity, inhibitory activity against peptidyl-prolyl isomerase or rotamase, antimalarial activity, antitumor activity, etc.

The Invention further provides a method for a dissolution test for a Solid formulation comprising a macrolide compound, wherein the test, a test solution used which contains a suitable amount of cellulose polymer. In general is the dissolution test to test the release characteristic of a medicinally active Substance which is present dissolved in a solid formulation, in accordance with "Dissolution Test", &lt;?page 12?&gt;process 2 (Paddle method, 50 rpm), JP XIII or "Dissolution Test" according to USP 23, NF18 or European Pharmacopoeia (3rd edition) performed. When performing a dissolution tests for a Formulation containing only a small amount of a macrolide compound contains, , the release of the macrolide compound based on their intrinsic content, even after several hours of 100% is not reached. If the amount of the macrolide compound is small, this is because the adsorption of the macrolide compound on the surfaces of Test vessel, filter, will have an increasing importance etc.. After such investigations the inventors have found that a suitable by the addition Amount of a cellulose polymer (such as HPMC, hydroxypropyl cellulose phthalate, MC, CMC-Na, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC) and so on) to the test solution and, if necessary, by adding phosphoric acid or the like to the test solution this not greater than at a pH of bring to 7, to an adverse effect of a progressive increase of pH on the stability To avoid the macrolide compound, the influence of adsorption the macrolide compound can be inhibited to the surfaces of the test device , in order to achieve a recovery rate of nearly 100th On preferred cellulosic polymer is Hyderoxypropylcellulose or equivalent from that. The preferred viscosity it is such that the solution a viscosity 75-150 cps shows, when 5.0 g is dissolved in 95 ml of water and the foam, if necessary, is removed by centrifugation, the viscosity of the solution with a rotational viscometer at 25 ± 0.1 ° C measured becomes. A corresponding hydroxypropyl cellulose having an average Molecular weight of about 100,000 is, for example, hydroxypropyl cellulose, Available from Aldrich is.

The "appropriate Amount "of cellulose polymer, which the test solution add is, is 0.001-0.1%, preferably 0.002 to 0.01%, 0.005% being most preferred, this being on the total amount the test solution based.

"Dissolution Test "method 2 (Paddle method), JP XIII and "Dissolution Test", according to USP 23, NF 18 or in European Pharmacopoeia (3rd edition) are well-known methods for testing the release kinetics of active ingredients of a pharmaceutical Solid product. These are dissolution tests using a specific vessel, paddle and other hardware, wherein the quantity the test solution Temperature of the test solution, the rotational speed, and other conditions are controlled. If necessary, the test is carried out with a test solution containing is adjusted to a suitable pH. According to the present invention is the pH is preferably not more than 7. In the present invention means "Dissolution Test, Method 2 (Paddle method, 50 rpm), JP XIII "a dissolution test, method 2 (paddle method) JP XIII ", which with stirring 50 revolutions per minute becomes. The corresponding descriptions in JP XIII, USP 23 (NF 18) and in European Pharmacopoeia (3rd edition) are by reference to these publications hereby introduced.

The Invention will be further described by way of examples. In the following examples, FK506 is admixed as a monohydrate, when the compositions contain FK506, although the amount of FK506 is expressed as the weight of FK506, not as the monohydrate weight. example 1 (reference) <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506 </entry><entry colname="2">1.0 mg</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">1.0 mg</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>2.0 mg</o></entry></row></tbody></tgroup></table></tables>

FK506 was dissolved in ethanol and HPMC 2910 was added to the solution reached by FK506 in a sufficiently leave to swell. Then the mixture was kneaded together. The obtained kneaded mixture was transferred to a stainless tray, in dried vacuum and ground with a coffee grinder. Subsequently the resulting powder size reduction subject, the following methods were used to prepare a solid dispersion composition (hereinafter designated as SDC) 1-1) to 1-6). <ul><li>(1) The ground powder was passed through a 250 .mu.m sieve and on the Screening remaining fraction was as SDC 1-1) (&gt; 250 microns) designated.</li><li>(2) through the screen by the process (1) which has passed Fraction was analyzed by a 1 80 microns happens sieve and remaining on the sieve fraction was as SDC 1-2) (180-250 microns), respectively.</li><li>(3) through the sieve at the process (2) has passed Fraction was measured by a 150 .mu.m happens sieve and remaining on the sieve fraction was as SDC 1-3) (150-180 .mu.m) referred.</li><li>(4) through the sieve at the process (3) has passed Fraction was measured by a 106 micron happens sieve and remaining on the sieve fraction was as SDC 1-4) (106-150 microns), respectively.</li><li>(5) through the sieve by the method (4) has passed Fraction was analyzed by a 75 micron Screening pas&lt;?page 13?&gt;Siert and the remaining on the sieve fraction was as SDC 1-5) (75-106 microns), respectively.</li><li>(6) through the sieve at the process (5) has passed Fraction was designated as SDC 1-6) (&lt;75 microns).</li></ul>

Example 2 (Reference)

SDC 1-2), which was obtained in Example 1, was sufficiently mixed with lactose (58.0 mg) are mixed and the resulting mixture was encapsulated, to produce a capsule.

Example 3 (Reference)

In a similar Manner as in Example 1, a ground powder of the following was SDC with particle size of 180 to 250 microns produced.

<img img-content="tb" img-format="tif" he="32" wi="129" file="00290001.tif" />

Further was SDC 3-1) was sufficiently mixed with lactose (58.7 mg) and the Resulting mixture was encapsulated, to prepare capsule 3-1). SDC 3-2) was sufficiently mixed with lactose (58.9 mg) and the Resulting mixture was encapsulated, to prepare capsule 3-2).

Example 4 (Reference)

In a similar Manner as for SDC 1-2) of Example 1, the following SDCs were prepared.

<img img-content="tb" img-format="tif" he="66" wi="153" file="00290002.tif" />

In a similar Manner as in Example 2, lactose (at an appropriate amount) and magnesium stearate (0.6 mg) was added to the respective SDCs, to prepare capsules of each 60.0 mg.

Example 5 (Reference)

In a similar Manner as in the SDC 1-2) of Example 1, a SDC using FK506 (1.0 mg) and HPMC 0 291 (1.0 mg) was prepared. In a similar Manner as in Example 2 were then the following additives, the SDC added to the capsules 5-1) to 5-4) each of 60.0 mg produce. &lt;?page 14?&gt;<img img-content="tb" img-format="tif" he="62" wi="152" file="00300001.tif" /> example 6 (reference) <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506 </entry><entry colname="2">1.0 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">0.3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>1.3g</o></entry></row></tbody></tgroup></table></tables>

FK506 was dissolved in ethanol and the mixture obtained HPMC 2910 was added to a sufficient to achieve swelling. Then the mixture was kneaded together. The obtained kneaded S was ubstanz transferred to a stainless tray, in dried vacuum and ground with a coffee grinder. The obtained Powder was size reduction subjected to produce the SDCs 6-1) to 6-6), the following Methods were used. <ul><li>(1) The ground Powder was passed through a 250 micron happens sieve and remaining on the sieve fraction was as SDC 6-1) (&gt; 250 microns), respectively.</li><li>(2) through the screen by the process (1) which has passed Fraction was measured by a 180 micron happens sieve and remaining on the sieve fraction was designated as SDC 6-2) (180-250 microns).</li><li>(3) The on the screen by the process (2) has passed fraction was filtered through a 150 micron happens sieve and remaining on the sieve fraction was designated as SDC 6-3) (150-180 microns).</li><li>(4) The through the screen by the process (3) has passed Fraction was measured by a 106 micron happens sieve and remaining on the sieve fraction was designated as SDC 6-4) (106-150 microns).</li><li>(5) through the sieve by the method (4) has passed Fraction was analyzed by a 75 micron happens sieve and remaining on the sieve fraction was designated as SDC 6-5) (75-106 microns).</li><li>(6) through the screen by the process (5) has passed Fraction was designated as SDC 6-6).</li></ul>

Example 7 (Reference)

SDC 6-4) (1.3 mg), which was obtained in Example 6 was mixed thoroughly with Lactose (58.1 mg) and magnesium stearate (0.6 mg) were mixed and the Resulting mixture was filled in capsules which were defined as capsule 7th

Example 8 (Reference)

In a similar Manner as in Example 1, the following SDCs produced with particle sizes of 180-250 microns.

&lt;?page 15?&gt;

<img img-content="tb" img-format="tif" he="47" wi="153" file="00310001.tif" />

In a similar Manner as in Example 7, each capsule is prepared by adding lactose (58.1 mg) and magnesium stearate (0.6 mg) were added. example 9 (reference) SDC 9 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">10 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">3 G</entry></row><row><entry colname="1">Calcium hydrogen phosphate</entry><entry colname="2">3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>16 g</o></entry></row></tbody></tgroup></table></tables> formulation 9 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 9</entry><entry colname="2">16 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">qs</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">7 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>700 g</o></entry></row></tbody></tgroup></table></tables>

FK506 was dissolved in ethanol, HPMC 2910 was added and thoroughly mixed with the obtained solution and then Calcium hydrogen phosphate has been added. After drying in vacuo overnight the mixture achieved a reduction in size was subjected, where a speed mill and a roll granulator were used. The resulting powder was with a sieve of 212 microns sieved and the fraction passing the sieve was referred to as SDC SDC 9. 9 was mixed with lactose and magnesium stearate, to the formulation 9 prepare. The formulation 9 was added to 350 mg in the no. 1 capsule and at 70 mg in the no. 5 gelatin capsule filled, which were defined as Formulations A and B, respectively. example 10 (Reference) SDC 10 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">10 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">3 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>16 g</o></entry></row></tbody></tgroup></table></tables> formulation 10 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 10</entry><entry colname="2">16 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">qs</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">7 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>700 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 9 was the SDC 10 and Formulation 10 prepared. &lt;?page 16?&gt; example 11 (Reference) SDC 11 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">10 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">3 G</entry></row><row><entry colname="1">Calciumhydrogenphosghat</entry><entry colname="2">3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>16 g</o></entry></row></tbody></tgroup></table></tables> formulation 11 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 11</entry><entry colname="2">16 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">qs</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">7 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>700 g</o></entry></row></tbody></tgroup></table></tables>

FK506 was dissolved in ethanol, HPMC 2910 was added and sufficiently mixed with the obtained solution, whereafter added calcium hydrogen phosphate has been. After the resulting mixture dried overnight in vacuo was, the mixture was subjected to a size reduction, which a speed mill and a roll granulator were used. The resulting powder was with a sieve of 250 microns and a sieve of 180 microns sieved. The fraction of 180-250 microns was as SDC 11 denotes. SDC 11, lactose and magnesium stearate were mixed together mixed to prepare the formulation of the eleventh The formulation 11 was added to 350 mg in the no. 1 capsule and at 70 mg in the no. 5 filled gelatin capsule, as Formulations C and D were described. example 12 SDC 12 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">Glycerol</entry><entry colname="2">98 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">20 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>120 g</o></entry></row></tbody></tgroup></table></tables> formulation 12 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 12</entry><entry colname="2">120 G</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">1.2 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>121.2 g</o></entry></row></tbody></tgroup></table></tables>

Glycerol was heated at 80 ° C melted, and with stirring FK506 was added in order to solve the FK506. To the obtained mixture was HPMC 2910 added with sufficient mixing and Resulting mixture was then transferred to a tray and was a spontaneous Cooling ditched. The solid substance obtained by cooling was with a coffee grinder ground and then sieved with a sieve of 500 microns. The through the sieve passing fraction was designated as SDC 12th SDC 12 was mixed with magnesium stearate, to prepare the formulation, which was then filled with 60.6 mg in the no. 5 capsule. The capsule Amount was designated as E formulation. example 13 SDC 13 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">Aminoalkyl methacrylate copolymer</entry><entry colname="2">6 G</entry></row><row><entry colname="1">Calcium hydrogen phosphate</entry><entry colname="2">2 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>10 g</o></entry></row></tbody></tgroup></table></tables> formulation 13 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 13</entry><entry colname="2">10 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">130 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

&lt;?page 17?&gt;

FK506 and aminoalkyl methacrylate copolymer were dissolved in ethanol, and then was was calcium hydrogen phosphate was added and the resulting mixture sufficiently mixed together. The mixture was under vacuum overnight dried in a mortar ground and with seven of 150 microns and sieved 106 microns, a fraction of 106-150 microns as SDC 13 achieve. SDC 13 was mixed with lactose and a formulation 13 prepared. This was then treated with 70 mg in the no. 5 gelatin capsule bottled, to the formulation F to manufacture. example 14 SDC 14 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">Aminoalkyl methacrylate copolymer (Eudragit RL)</entry><entry colname="2">4.6 G</entry></row><row><entry colname="1">Aminoalkyl methacrylate copolymer (Eudragit RS)</entry><entry colname="2">1.4 G</entry></row><row><entry colname="1">Calcium hydrogen phosphate</entry><entry colname="2">2 q</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>10 g</o></entry></row></tbody></tgroup></table></tables> formulation 14 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 14</entry><entry colname="2">10 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">130 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 13 was the SDC 14 with particle sizes of 106-150 microns and Formulation 14 produced.

Then was the formulation 14 with 70 mg in the no. 5 gelatin capsule bottled, to the formulation G to produce. example 15 SDC 15 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">Aminoalkyl methacrylate copolymer (Eudragit RL)</entry><entry colname="2">3 G</entry></row><row><entry colname="1">Aminoalkyl methacrylate copolymer (Eudragit RS)</entry><entry colname="2">3 G</entry></row><row><entry colname="1">Calciumhvdrogenphosphat</entry><entry colname="2">2 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>10 g</o></entry></row></tbody></tgroup></table></tables> formulation 15 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 15</entry><entry colname="2">10 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">130 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 1 was 3 SDC 1 5 having particle sizes 106-150 microns and Formulation 15 produced. Formulation 15 was charged with 70 mg bottled in the no. 5 gelatin capsule to the formulation H produce. example 16 SDC 16 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">ethylcellulose</entry><entry colname="2">0.4 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">6 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>8.4g</o></entry></row></tbody></tgroup></table></tables> formulation 16 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 16</entry><entry colname="2"> 8.4 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">131.6 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

&lt;?page 18?&gt;

FK506 and ethyl cellulose were dissolved in ethanol, and then was Lactose added. The resulting mixture was in a sufficient Dimensions mixed. The mixture was transferred in vacuo Dried overnight in a mortar ground and with seven of 150 microns and 106 microns sieved, to prepare a fraction of 106-150 .mu.m as SDC sixteenth SDC 16 was mixed with lactose and prepared as Formulation 16, and then 70 mg were filled into the no. 5 gelatin capsule to the formulation produce I. example 17 SDC 17 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">ethylcellulose</entry><entry colname="2">1 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">6 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>9 g</o></entry></row></tbody></tgroup></table></tables> formulation 17 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 17</entry><entry colname="2">9 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">131 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 16 was the SDC 17 with particle sizes of 106-150 microns and Formulation 17 produced. Formulation 17 was charged with 70 mg bottled in the no. 5 gelatin capsule to the formulation J produce. example 18 SDC 18 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">ethylcellulose</entry><entry colname="2">0.4 G</entry></row><row><entry colname="1">hydroxypropylmethylcellulose</entry><entry colname="2">0.6 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">6 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>9 g</o></entry></row></tbody></tgroup></table></tables> formulation 18 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 18</entry><entry colname="2">9 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">131 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 16 SDC 18 was mixed with particle sizes of 106-150 microns and Formulation 18 produced. Formulation 18 was charged with 70 mg bottled in the no. 5 gelatin capsule to the formulation K produce. example 19 SDC 19 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">2 G</entry></row><row><entry colname="1">ethylcellulose</entry><entry colname="2">0.6 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">0.6 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">6 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>9.2g</o></entry></row></tbody></tgroup></table></tables> formulation 19 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 19</entry><entry colname="2">9.2 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">130.8 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>140 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 16 was 19 SDC with particle sizes of 106-150 microns and Formulation 19 produced. Formulation 19 was charged with 70 mg bottled in the no. 5 gelatin capsule to &lt;?page 19?&gt;the formulation L prepare example 20 SDC 20 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">10 G</entry></row><row><entry colname="1">ethylcellulose</entry><entry colname="2">3 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">3 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">50 G</entry></row><row><entry colname="1">total </entry><entry colname="2"><o>66 g</o></entry></row></tbody></tgroup></table></tables> formulation 20 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 20</entry><entry colname="2">66 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">qs</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">7 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>700 g</o></entry></row></tbody></tgroup></table></tables>

FK506 was dissolved in ethanol and ethyl cellulose was added and dissolved. HPMC 2910 and lactose were the solution reached added and sufficiently mixed. After the mixture overnight in a Vacuum dried, the obtained mixture to a size reduction was using a speed mill and a roll granulator subjected. The resulting powder was sieved with a sieve of 250 microns. The fraction which passed through the sieve was designated as SDC 20th SDC 20, lactose and magnesium stearate were mixed together, to produce the formulation 20th Formulation 20 was to bottled 350 mg in the no. 1 capsule and 70 mg in the no. 5 gelatin capsule formulations as M or N were designated. example 21 SDC 21 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">10 G</entry></row><row><entry colname="1">ethylcellulose</entry><entry colname="2">3 G</entry></row><row><entry colname="1">HPMC 2910</entry><entry colname="2">3 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">20 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>36 g</o></entry></row></tbody></tgroup></table></tables> formulation 21 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 21</entry><entry colname="2">36 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">qs</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">7 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>700 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as to recordable 20 was a fraction the sieve happened 212 microns, as SDC 21 designated and formulation 21 was prepared. The Formulation 21 was then added to 350 mg in the no. 1 gelatin capsule and 70 mg packaged in the no. 5 gelatin capsule to the formulations O or P to achieve. example 22 SDC 22 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">F K506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Sucrose fatty acid ester (HLB = 6) (DK ester F-50)</entry><entry colname="2">1 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>2 g</o></entry></row></tbody></tgroup></table></tables> formulation 22 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 22</entry><entry colname="2">2 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">68 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

&lt;?page 20?&gt;

FK506 was dissolved in ethanol / acetone (1/1). After heating the solution to 75 ° C was a sucrose fatty acid ester added, dissolved and then cooled to room temperature. The mixture was stirred overnight ground and with seven of 150 microns and 106 microns sieved, to prepare a fraction of 106-150 .mu.m as SDC 22nd SDC 22 was mixed with lactose and prepared as Formulation 22, which was then filled with 70 mg in the no. 5 gelatin capsule, to the formulation to produce Q. example 23 SDC 23 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Sucrose fatty acid ester (HLB = 6) (DK ester F-50)</entry><entry colname="2">0.75 G</entry></row><row><entry colname="1">Sucrose fatty acid ester (HLB = 2) (DK ester F-20W)</entry><entry colname="2">0.25 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>2 g</o></entry></row></tbody></tgroup></table></tables> formulation 23 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 23</entry><entry colname="2">2 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">68 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 22 was 23 SDC with particle sizes of 106-150 microns and Formulation 23 produced. Formulation 23 was then treated with 70 mg packaged in the no. 5 gelatin capsule to the formulation R produce. example 24 SDC 24 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Sucrose fatty acid ester (HLB = 1) (DK ester F-10)</entry><entry colname="2">1 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">1 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>3 g</o></entry></row></tbody></tgroup></table></tables> formulation 24 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 24</entry><entry colname="2">3 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">67 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 22 was 24 SDC with particle sizes of 106-150 microns and Formulation 24 produced. The formulation was then 24 to 70 mg filled into the no. 5 gelatin capsule to the formulation S produce. example 25 SDC 25 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Sucrose fatty acid ester (HLB = 1) (DK ester F-10) 1 g</entry><entry colname="2" /></row><row><entry colname="1">lactose</entry><entry colname="2"> 3 G</entry></row><row><entry colname="1">total </entry><entry colname="2"><o>5 g</o></entry></row></tbody></tgroup></table></tables> formulation 25 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 25</entry><entry colname="2">5 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">65 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 22 was 25 SDC with particle sizes of 106-150 microns and &lt;?page 21?&gt;the 25 formulation prepared, the formulation was 25 to 70 mg bottled in the no. 5 gelatin capsule to the formulation T produce. example 26 SDC 26 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Sucrose fatty acid ester (HLB = 1) (DK ester F-10)</entry><entry colname="2">1 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">5 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>7 g</o></entry></row></tbody></tgroup></table></tables> formulation 26 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 26</entry><entry colname="2">7 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">63 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 22 was 26 SDC with particle sizes of 106-150 microns and Formulation 26 produced. The formulation was then 26 to 70 mg filled into the no. 5 gelatin capsule to the formulation U produce. example 27 SDC 27 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Tetra glycerol trifatty acid esters</entry><entry colname="2">30 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">15 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>46 g</o></entry></row></tbody></tgroup></table></tables> formulation 27 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 27</entry><entry colname="2">46 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">24 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

On Tetra glycerol trifatty acid esters, by heating at 80 ° C was melted, was dissolved with added FK506. Lactose was added mixed and then allowed to cool to a bowl. The scoring Solid substance was ground with a coffee grinder and sieving of 150 microns and 1 06 microns sieved, to prepare a fraction of 106-150 .mu.m as SDC 27th SDC 27 was mixed with lactose and prepared as Formulation 27th The formulation was then 27 to 70 mg into the no. 5 gelatin capsule bottled, to produce the formulation V. example 28 SDC 28 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Tetra glycerol trifatty acid esters</entry><entry colname="2">30 G</entry></row><row><entry colname="1">Polysolbat</entry><entry colname="2">0.3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>31.3 g</o></entry></row></tbody></tgroup></table></tables> formulation 28 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 28</entry><entry colname="2">31.3 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">38.7 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

In a similar Manner as in Example 27 was 28 SDC with particle sizes of 106-150 microns produced. Further, the formulation 28 was prepared which was then 70 mg in the no. 5 gelatin capsule was filled to the formulation W produce. &lt;?page 22?&gt; example 29 SDC 29 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506</entry><entry colname="2">1 G</entry></row><row><entry colname="1">Tetra glycerol trifatty acid esters</entry><entry colname="2">1 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>5 g</o></entry></row></tbody></tgroup></table></tables> formulation 29 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">SDC 29</entry><entry colname="2">5 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">65 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>70 g</o></entry></row></tbody></tgroup></table></tables>

ethanol was added to a tetraglycerol trifatty acid esters. The scoring Mixture was melted by heating to 40 ° C and FK506 was added, and melted with stirring. Lactose was added mixed and then allowed to cool in a bowl. The scored, solid substance was ground by a coffee mill, dried in vacuo over night dried and screened with sieves of 150 microns and 106 microns, a fraction of 106-150 microns as SDC 29 produce. SDC 29 was mixed with lactose and a formulation 29 prepared. Then the formulation 29 to 70 mg in No. was. 5 filled gelatin capsule, to the formulation to produce X. example 30 (Reference) formulation 30 <tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">FK506 fine powder</entry><entry colname="2">0.5 G</entry></row><row><entry colname="1">lactose</entry><entry colname="2">29.2 G</entry></row><row><entry colname="1">magnesium stearate</entry><entry colname="2">0.3 G</entry></row><row><entry colname="1">total</entry><entry colname="2"><o>30 g</o></entry></row></tbody></tgroup></table></tables>

crystals of FK506 were ground with a jet mill and then with Lactose and magnesium stearate were mixed to prepare the formulation 30th Then the formulation 5 was 30 to 60 mg in No.. Gelatine capsules bottled, the formulation produce Z. The range of particle size of the fine Powder of FK506, which had been crushed with the jet mill was, 1-10 microns and the average particle size was about 3 microns.

Example 31 (Reference)

test solution

Test sample

<ul><li>(1) Formulations A and C were in accordance with the above mentioned Examples prepared.</li><li>(2) Control formulation (rapid-release formulation) a 1 mg capsule formulation was that the following ingredients included. It was in a similar Manner as Examples 1 and 2 of WO 91/19495 prepared by the components (e) and (f) with the solid dispersion composition were mixed which contained the following ingredients (a) to (d). The formulation was then encapsulated.</li></ul>

<img img-content="tb" img-format="tif" he="46" wi="108" file="00450001.tif" />

&lt;?page 23?&gt;

test method

According to Japanese Pharmacopoeia, 13th edition, Dissolution Test, Nr. 2 (Paddle method, 50 rpm), a test was carried out under aqueous use of a 0.005% Hydroxypropyl cellulose solution had been adjusted to a pH of 4.5. The data obtained are shown below. <img img-content="tb" img-format="tif" he="81" wi="152" file="00450002.tif" /><tables><table><tgroup cols="2"><colspec colname="1" colwidth="1*" /><colspec colname="2" colwidth="1*" /><colspec colnum="1" colname="1" colwidth="3.346in" colsep="0" /><colspec colnum="2" colname="2" colwidth="3.346in" colsep="0" /><tbody><row><entry colname="1">time (Hours.)</entry><entry colname="2">control (%)</entry></row><row><entry colname="1">0</entry><entry colname="2">0.0</entry></row><row><entry colname="1">0.17</entry><entry colname="2">30.1</entry></row><row><entry colname="1">0.5</entry><entry colname="2">68.4</entry></row><row><entry colname="1">1</entry><entry colname="2">92.8</entry></row><row><entry colname="1">2</entry><entry colname="2">100.1</entry></row></tbody></tgroup></table></tables>

example 32

In a similar Manner as in Example 31, the dissolution test was performed. The various parameters in Weibull function and the values ​​of T 63.2% were obtained by calculation.

&lt;?page 24?&gt;

Result <img img-content="tb" img-format="tif" he="131" wi="152" file="00460001.tif" />

<img img-content="tb" img-format="tif" he="32" wi="152" file="00470001.tif" />

Example 33 (Reference)

Oral absorbency

Test sample

<ul><li>(1) Formulations B and D were prepared as in those mentioned above Examples prepared.</li><li>(2) Control formulation (the same control formulation as in Example 31).</li></ul>

test method

The Test samples were orally 6 cynomologous monkeys (1 mg / monkey as an FK506 dose) given to the FK506 blood concentration after the administration to determine. 17 hours prior to administration of the food was the feed table the cynomologous monkeys body weight had about 6 kg removed. Then the animals starved to 12 Hours after administration. Water ad libitum before the start the test is supplied by the administration of the test samples and thereafter. at the dosage was added water (20 ml) simultaneously animals. At predetermined times after dosing, 1 ml of blood out &lt;?page 25?&gt;removed the Vorderarmvene using a sterile syringe and placed in a plastic vessel, the heparin. The sample was stored at -80 ° C until the start of determination the drug concentration kept. The whole blood concentration FK506 was a FK506-specific enzyme immunoassay (EIA) determined, which is known from JP-A-1-92659. The publication which is hereby incorporated and forms part of the present description.

average value

<img img-content="tb" img-format="tif" he="97" wi="142" file="00480001.tif" />

The maximum blood concentration (Cmax) was defined as the maximum Amount of drug in whole blood. Tmax is the time required for the achievement the maximum blood concentration is necessary. MRT is defined as the average retention time defined. The area under the Blood concentration-time curve (AUC) was with the trapezoid calculated. As an indicator of the variation of oral absorbability was further CV (standard deviation / average calculated in%).

test results <img img-content="tb" img-format="tif" he="58" wi="153" file="00480002.tif" />

example 34

Similarly Manner as in Example 33 was oral absorbency of the different formulations according to the present invention certainly.

&lt;?page 26?&gt;

Results

<img img-content="tb" img-format="tif" he="90" wi="153" file="00490001.tif" />

The show above results that the principles for the above experiments Formulations after oral administration a smaller Cmax and sufficiently extended Tmax and MRT have than the formulation with rapid release (Control). In comparison with the formulation having a quick release were the AUC of the above formulations are almost the same or greater. The above formulations with delayed Release showed at the individual test animals minor variations of Cmax and / or AUC compared to the formulation with faster Release.

According to the invention the present application may be a slight variation in the test animals compliance with the maximum blood concentration or the area after under the blood concentration-time curve of the macrolide oral dosage can be determined in comparison with a formulation rapid release. Therefore is an indicator of the variation of the Blutabsorbierfähigkeit the macrolide compound used, namely the standard deviation / average (CV in%) of the maximum blood concentration or the area under the blood concentration-time curve. The term "low Variation means " a small CV value thereof, and in particular this term means that the CV value is smaller as the value of the above-described formulation with rapid release.

The Publications the patents, patent applications and references that here in the mentioned application are encompassed by the description herein with.