KR100463356B1 - Process for Encapsulation of Caplets in a Capsule and Solid Dosage Forms Obtainable by Such Process - Google Patents

Abstract

The present invention provides a method for producing a capsule comprising: a) providing hollow capsule portions, b) filling one or more caplets into at least one of the capsule portions, c) joining the capsule portions together, and d) combining the combined capsule portions. A method of encapsulating a caplet, comprising the step of cooling shrinkage treatment. Solid formulations obtainable in this way are unopenable in that they cannot be opened in a reassembled manner without an opening process.

Description

Process for Encapsulation of Caplets in a Capsule and Solid Dosage Forms Obtainable by Such Process}

The present invention relates to a method of encapsulating a caplet, and to a solid dosage form obtainable by the method, and more particularly to a method of preparing a tamper-proof capsule containing a pharmaceutically active composition. .

Many oral drugs have been prepared in the so-called caplet form, which the patient can swallow while taking the drug. However, caplets are not as easily swallowed by the patient as capsules, eg gelatin coated capsules. It is also desirable to encapsulate the caplets, since capsule coatings sometimes provide a neutralized taste as opposed to the caplets themselves which contain, for example, a bitter taste pharmaceutical substance. That is, patients, especially children, do not try to swallow the caplets by themselves. Thus, there have been attempts to encapsulate the caplets with gelatin coating.

Berta, US Pat. No. 4,867,983, describes a method of immersing a gelatin-coated caplet twice. This method involves coating a solid core, such as a caplet, with a first gelatin coating on one end, followed by a second gelatin coating on the other end thicker than the first so that the halves resemble hollow capsules with interlocking halves. Include procedures. The second thicker gelatin coating may be provided with a single gelatin coating from a bath of higher viscosity than the bath used to provide the first gelatin coating. Alternatively, the second gelatin coating may be provided by immersing twice so that the gelatinous material film or gelatin film is formed. This method is disadvantageous by this known coating in that the gelatin coating and color distribution are not evenly distributed on the caplets. Moreover, overlaying different coatings results in color change of the coatings. In addition, the immersion edges obtained by this known method tend not to be straight. In addition, when the coated caplets are stored in a dry state and / or at a high temperature, the coating according to the patent is crushed under stress. As a result, the dip coating method of US Pat. No. 4,867,983 is time consuming and expensive.

In US Pat. No. 5,081,822 to Boyd et al., Automatic caplet chargers for filling conventional gelatin capsules with caplets are known. However, the capsule produced by this automatic caplet charger has the disadvantage of easy artificial manipulation. The encapsulation of the capsule should be carried out by additional gelatin shelling or by sealing the caplet to the capsule, for example using an adhesive as described in US Pat. No. 4,928,840 or European Patent Application 0435726. Such additional treatment in the capsule may potentially lead to the addition of non-drug substances into the capsule. On the one hand, if an aqueous base adhesive is used to seal the capsule halves together, the capsule as well as the caplet can be modified. On the other hand, when using an adhesive containing an organic solvent, the capsule will easily break as a result. Finally, if one half of the capsule is combined with the other by thermal shrinkage, there will be a visible gap between the capsule halves.

It is therefore an object of the present invention to provide a method of putting a caplet in a capsule that is not opened. It is a further object of the present invention to provide a method for easily preparing an unopened solid formulation which is cost effective. Another object of the present invention is to provide a solid dosage form comprising a caplet covered with a capsule. It is a further object of the present invention to provide pharmaceutical formulations which are more resistant to breakdown than already known products. Another object of the present invention is to provide a solid formulation that is not openable.

Summary of the Invention

According to a first aspect of the present invention, the present invention provides a method for encapsulating a caplet by cooling shrinking the capsule portions filled with the caplet together. According to another aspect the present invention provides a solid dosage form obtainable by such a method. The solid dosage form according to the invention is impossible to open in the sense that the caplets contained in the capsule cannot be taken out of the capsule without breaking the capsule.

Furthermore, the method according to the invention provides a capsule product comprising several parts which are joined together in such a way that there is no visible gap between the capsule parts after the cooling shrinkage process. The solid dosage forms of the present invention are easily swallowed by patients because the surface is completely smooth. More specifically,

a. Providing hollow capsule portions,

b. Filling one or more caplets into at least one of the capsule portions,

c. Joining the capsule portions to each other, and

d. A method of placing a caplet in a capsule is provided that includes cooling shrinking the combined capsule portions.

Moreover, solid formulations are disclosed which include caplet and capsule coatings obtainable by this method.

Description of the Preferred Aspects of the Invention

The capsule shell surrounding the caplet preferably comprises two shell halves, the body and the cap. Other capsules consisting of two or more parts are also possible. The capsule is typically a generally cylindrical hollow shell of diameter and length sufficient to allow the caplet to fit properly into the empty capsule. The clearance between the capsule shell and the caplet is preferably about +0.5 mm. According to a particularly preferred aspect of the invention, the gap between the capsule shell and the caplet is in the range of about 0 to about -0.5 mm, which means that the caplet is pressed in the capsule.

Particularly preferred methods of the invention are carried out as follows. After preparing the hollow capsule portions, the relative humidity is preserved in a humid state in the range of about 40 to about 90%, specifically about 60 to about 80%, so that the water content of the capsule shell is about 14 to about 19% by weight, preferably May be held in the range of about 15 to about 18 weight percent, more preferably in the range of about 16 to about 18 weight percent, or re-humidified to the water content prior to feeding into the capsule filling machine.

The first capsule shell portion is then orientated and left wet in the charger at a water content as described above while joining the first capsule shell with the caplet having a water content ranging from about 0 to about 12 weight percent.

The second or additional capsule portion is treated in the same way as the first. Finally, the encapsulated formulation has a relative humidity in the range of about 20 to about 40% and a temperature in the range of about 15 to about 60 ° C, preferably about 15 to about 40 ° C, more preferably about 18 to about 25 ° C. To dry.

Caplets having a low water content in the range of about 0 to about 6 weight percent, more preferably about 0 to about 3 weight percent, are particularly suitable for use in the methods of the present invention. The caplet has a conical end that can be easily inserted into one half of the capsule. After the parts of the capsule have been dried and shrunk together, the capsule can be coated with an additional film, which coating can be enteric.

The capsule shell material may be a hydrophilic polymer, with gelatin being preferred. Other suitable capsule shell materials include starch, casein, chitosan, soy protein, safflower protein, alginate, gellan rubber, carrageenan, xanthan gum, phthalic acid gelatin, succinate gelatin, cellulose phthalate-acetate, polyvinylacetate, hydroxy Polymerized products of propyl methylcellulose, polyvinylacetate-phthalate, acrylic acid or methacrylic acid esters or mixtures thereof. The capsule shell material may also include from about 0 to about 40% by weight of the hydrophilic polymer, with a pharmaceutically acceptable plasticizer. Plasticizers that can be used are polyethylene glycol, glycerol, sorbitol, dioctyl-sodium sulfosuccinate, triethyl citrate, tributyl citrate, 1,2-propylene glycol, mono-, di, or tri-acetate of glycerol or May be selected from mixtures thereof.

In addition, the capsule shell material may comprise a pharmaceutically acceptable lubricant in the range of about 0 to about 10% by weight of the hydrophilic polymer. The lubricant may be selected from aluminum stearate, calcium stearate, magnesium stearate, tin stearate, talc, sodium lauryl sulfate, lecithin, mineral oil, stearic acid or silicone or mixtures thereof.

Moreover, the capsule shell material may comprise a pharmaceutically acceptable colorant in the range of about 0 to about 10% by weight of the hydrophilic polymer. The colorant may be selected from azo-quinophthalone-, triphenylmethane-, xanthene-dye, iron oxide, iron hydroxide, titanium dioxide or natural dyes or mixtures thereof. More suitable colorants include sunset yellow, allura red, amaranth, cochineal red, azogeranine, tarrazine, brilliant black, canthaxanthin, patent blue, fast green, brilliant Blue, acid green, erythrosin, quinoline yellow, indigotin, curcumin or carbon black.

In addition, the capsule shell material may comprise a pharmaceutically acceptable extender in the range of about 0 to about 95% by weight of the hydrophilic polymer. Extenders include sunflower protein, soy protein, cotton seed protein, peanut protein, rapeseed protein, lactose, gum arabic, acrylate or methacrylate, cellulose acetyl phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methyl Cellulose phthalate, hydroxymethylcellulose, polyvinylpyrrolidone, cellac, bentonite, polyvinyl acetate acetate, phthalic acid treated gelatin, succinic acid treated gelatin, agar, hydroxyalkyl starch or mixtures thereof.

Solid pharmaceutical formulations according to the invention may also comprise a coating selected from celasate, polyvinyl acetate phthalate, methacrylic acid polymers, hypromellose phthalate, hydroxyalkyl methyl cellulose phthalate or mixtures thereof.

The capsule portions of the solid dosage forms of the invention may each be the same or different in length and / or color. In terms of contact between the capsule portions, the solid dosage form can form a band or can be easily divided. The caplets included in the capsule may have steps or grooves preformed within the splitting points of the capsule. In order to further refine the caplets contained in the capsules, the caplets may be coated with an acceptable coating for tablet processing. In some cases, however, uncoated caplets are preferred. Improved contact between the inner shell and caplet of the capsule portions can be obtained by adhesive treating the inner shell and / or caplet surface. A suitable technique for applying the adhesive is to spray the adhesive onto the shell and caplet just prior to assembly. Suitable adhesives are, for example, aqueous tackidex or gelatin solutions.

Another aspect of the invention is to provide an encapsulated formulation in which the capsule shell halves do not completely cover the entire caplet, meaning that the caplets are longer than the combined length of the shell halves. This will give the capsule further advantageous features. For example, if each capsule half has a different color and the caplet has any third color, you will get a three-color capsule, and the shell half has the same color and the caplet has a different color. If so, you will get a capsule with a colored band formed. The second optional feature can be obtained using enteric capsule capsule halves. In this case, a delayed release capsule will be obtained, initially releasing the drug from the small release band between the shell halves and later from the capsule opening.

Another aspect of the invention is the use of the above described water conditioning and rehumidification in conventional encapsulation machines with all types of conventional hard gelatin capsule types. The method of the present invention provides even better filling results using chargers in high temperature and dry areas, especially for loading all kinds of fillers such as powders, pellets, liquids, microcapsules, tablets and the like. The preferred method in this case is carried out as follows: the hollow capsules and the preferred capsules are assembled in a pre-closed state and stored in a humid state with a humidity of 40 to 90%, preferably 60 to 80% relative humidity after manufacture. To have a water content of about 14 to about 19 weight percent of the capsule shell, preferably about 15 to about 18 weight percent, and most preferably about 16 to about 18 weight percent, or before opening and sorting in a capsule filling machine. Re-humidify until several minutes. The capsules are then stored under the moist state of the water content in the charger during orientation adjustment and filling with the desired product. In the same way the capsule cap is oriented and stored at this moisture content during assembly into the filled capsule. Finally, the capsules are dried at a relative humidity of 20-40% and at a temperature of about 15 to about 60 ° C, preferably about 15 to 40 ° C, most preferably about 18 to about 25 ° C.

Solid dosage forms according to the invention may comprise, for example, pharmaceutical or agrochemically active compositions. Solid dosage forms may also include, for example, foodstuffs or dye compositions. When the solid dosage form of the invention comprises a pharmaceutical composition, the active substance of the composition is, for example, betamethasone, thioctic acid, sotalol, salbutamol, norphenephrine, silymarin, dihydroergotamine, buflomedyl, Etofibrate, indomethacin, oxazepam, acetyldigitoxin, phyroxicam, haloperidol, isosorbide mononitrate, amitriptyline, diclofenac, nifedipine, verapamil, pyrithiol, nitrendipine, doxycycline, bromine Hexine, methylprednisolone, clonidine, fenofibrate, allopurinol, pyrenzepine, levothyroxine, tamoxifen, methyldigoxin, o- (β-hydroxyethyl) -rutoside, propicillin, acyclovirmonitrate, paracetamolol, Naphthydrofuryl, pentoxifylline, propaphenone, acebutolol, 1-thyroxine, tramadol, bromocriptine, loperamide, ketopinene, phenoterol, ca-dobesylate, propranolol, mo Cyclin, Nisergoline, Ambroxol, Metoprolol, β-Sitosterin, Enalapril Hydrogenmaleate, Bezafibrate, Isosorbide Dinitrate, Gallopamil, Xanthinol Nicotinate, Digitoxin , Flunitrazepam, bencyclane, depanthenol, pindolol, lorazepam, diltiazem, pyracetam, phenoxymethylphenicillin, furosemide, bromazepam, flunarizine, erythromycin, metoclopramide, ace Methacin, ranitidine, biperdene, metamizol, doxepin, dipotassium-chlorasepart, tetrazepam, esturamustine phosphate, terbutaline, captopril, maprotilin, prazosin, atenolol, glybene Clammid, cefachlor, ethyllephrine, cimetidine, theophylline, hydromorphone, ibuprofen, primidone, clovazam, oxaceprolol, methoxyprogesterone, flcainide, Mg-pyridoxal-5-phosphate glutamate, Jaime Romone, etophylline clofibrate, vincarmine, cinnarizine, diazepam, ketoprofen, flufenticol, molsidomine, glyborneuride, dimethindene, melferon, soquinolol, dihydrocodeine, clomethazole, Clemastine, Glysoxide, Calidinogenase, Oxypedrine, Baclofen, Carboxymethylcystsin, Thioredoxin, Betahistine, 1-Tryptophan, Myrtol, Bromelain, Prenylamine, Sala Zosulpapyridine, Astemizole, Sulpyrid, Bengerazide, Dibenzepine, Acetylsalicylic acid, Myconazole, Nisstatin, Ketoconazole, Sodium Picosulfate, Cholestyramate, Gepicbrozil, Rifampin, Fluorocortolone, Mexyl Retin, Amoxicillin, Terpenadine, Mucopolysaccharide Polysulfuric Acid, Triazolam, Mianserine, Tiapropenceaure, Amezinium Methyl Sulfate, Mefloquine, Probucol, Quinidine, Carbamazepine, Mg-1-Aspar Tate, penbutolol, blood Tanides, amitriptyline, caprolone, sodium valproate, mebeberine, bisacodeyl, 5-amino-salicylic acid, dihydralazine, magaldrate, fenprocomon, amantadine, naproxen, carteolol, pamotidine , Methyldopa, auranopine, estriol, nadolol, levomepromazine, doxorubicin, medophenoxat, azathioprine, flutamide, norfloxacin, pendylin, prazimallium bitartrate, aescin , Acromycin, anipamil, benzocaine, β-carotene, chloramphenicol, chlorodiazepoxide, chlormadinone acetate, chlorothiazide, cinnarizine, clonazepam, codeine, dexamethasone, dicoumarol, digoxin, drotaberine , Gramicidine, griseofulvin, hexobarbital hydrochlorothiazide, hydrocortisone, hydroflumethiazide, ketoprotene, ronetyl, medazepam, mepruside, methanedrostenolone, sulfa Lean, nalidic acid, nitrazepam, nitrofurantoin, estradiol, papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, prednisone, reserpin, spironolactin, streptomycin, sulfamethiazole, sulfamethazine , Sulfamethoxazole, sulfamethoxydiazinone, sulfatiazole, sulfisoxazole, testosterone, tolazamide, tolbutamide, trimethoprim, tyrotricin or mixtures thereof.

The purpose of the above description is to illustrate some forms and uses of the present invention and not to limit it in any way. It will be apparent to those skilled in the art that various modifications and variations of the methods and products of the present invention are possible without departing from the spirit or scope of the invention.

Claims (46)

a. Providing hollow first and second capsule shell portions, b. Filling one or more caplets into at least one of the capsule portions, c. Joining the capsule portions to each other, and d. A method of encapsulating a caplet comprising cooling shrinkage of the combined capsule portions, Here, the hollow capsule parts are preserved in a humid state in which relative humidity is in the range of about 40 to about 90% after preparation, so that the water content of the capsule shell is in the range of about 14 to about 19% by weight (range of about 16 to about 18% by weight) Or re-humidify with the moisture content prior to feeding it to the capsule charger, orient the first capsule portion, and assemble the caplet and the first capsule portion with a water content in the range of about 0-12 wt%. The moisturizer as described above is kept wet in the charger and the second capsule portion is treated in the same manner and the encapsulated formulation is in the relative humidity range of about 20 to about 40% and in the temperature range of about 15 to about 60 ° C. How to dry in the. The method of claim 1, wherein the caplet comprises a compressed material. The method of claim 1 wherein the water content of the capsule shell is in the range of at least about 15% and less than about 16% by weight of the capsule shell weight. The method of claim 1, wherein the encapsulated formulation is dried at a temperature in the range of about 15 to about 40 ° C. The method of claim 4, wherein the encapsulated formulation is dried at a temperature in the range of about 18 to about 25 ° C. 6. The method of claim 1, wherein the capsule portions are maintained at a relative humidity within the range of about 60 to about 80% during the step of feeding, orienting and engaging the capsule charger. The method of claim 1 wherein the water content of the caplet ranges from about 0 to about 6 weight percent. The method of claim 1 wherein the water content of the caplet ranges from about 0 to about 3 weight percent. The method of claim 1, wherein the caplet has a conical end. The method of claim 1, wherein the gap between the capsule portion and the caplet ranges from 0 to 0.5 mm. The method of claim 1, wherein the gap between the capsule portion and the caplet ranges from about 0 to −0.5 mm. The method of claim 1, wherein the encapsulated formulation is coated with a film after the capsule portions are dried and shrunk. The method of claim 12, wherein the coating is enteric. The method of claim 6, wherein the capsule portion material comprises a hydrophilic polymer. The method of claim 6 wherein the capsule portion material is gelatin, starch, casein, chitosan, soy protein, safflower protein, alginate, gellan gum, carrageenan, xanthan gum, phthalate treated gelatin, succinic acid treated gelatin, cellulose phthalate-acetate, polish The polymer is selected from the group consisting of nile acetate, hydroxypropyl methylcellulose, polycinyl acetate-phthalate, acrylic acid or methacrylic acid esters, and mixtures thereof. The method of claim 14, wherein the capsule portion material comprises a pharmaceutically acceptable plasticizer in the range of about 0 to about 40% by weight of the hydrophilic polymer. 17. The mono-, di, or tri of claim 16, wherein the plasticizer is polyethylene glycol, glycerol, sorbitol, dioctyl-sodium sulfosuccinate, triethyl citrate, tributyl citrate, 1,2-propylene glycol, glycerol -Acetates, and mixtures thereof. The method of claim 14, wherein the capsule portion material comprises a pharmaceutically acceptable lubricant in the range of about 0 to about 10% by weight of the hydrophilic polymer. 19. The lubricant of claim 18 wherein the lubricant is selected from the group consisting of aluminum stearate, calcium stearate, magnesium stearate, tin stearate, talc, sodium lauryl sulfate, lecithin, mineral oil, stearic acid or silicone, and mixtures thereof. How to be. The method of claim 14, wherein the capsule portion material comprises a pharmaceutically acceptable colorant in the range of about 0 to about 10% by weight of the hydrophilic polymer. The method of claim 20, wherein the colorant is selected from the group consisting of azo-quinophthalone-, triphenylmethane-, xanthene-dye, iron oxides or iron hydroxides, titanium dioxide or natural dyes, and mixtures thereof. 21. The colorant of claim 20 wherein the colorants are sunset yellow, allura red, amaranth, cochineal red, azogeranine, tarrazine, brilliant black, canthaxanthin, patent blue, fast green, brilliant blue, acid green, erythro Cin, quinoline yellow, indigotin, curcumin or carbon black. The method of claim 14, wherein the capsule portion material comprises a pharmaceutically acceptable extender in the range of about 0 to about 95% by weight of the hydrophilic polymer. The method of claim 3, wherein the capsule portion material comprises an extender. The method of claim 24 wherein the extender is sunflower protein, soy protein, cotton seed protein, peanut protein, rapeseed protein, lactose, gum arabic, acrylate or methacrylate, cellulose acetyl phthalate, hydroxypropyl cellulose, hydroxypropyl methyl With cellulose, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose, polyvinylpyrrolidone, cellac, bentonite, polyvinyl acetate acetate, phthalic acid gelatin, succinic acid gelatin, agar agar, hydroxyalkyl starch, and mixtures thereof And selected from the group consisting of: The method of claim 12, wherein the coating is selected from the group consisting of celasate, polyvinyl acetate phthalate, methacrylic acid polymers, hypromellose phthalate, hydroxyalkyl methyl cellulose phthalate, and mixtures thereof. The method of claim 6, wherein the lengths of the first and second capsule portions are the same or different from each other. The method of claim 6, wherein the colors of the first and second capsule portions are the same or different from each other. The method of claim 6, wherein a band is formed on the contact surface of the capsule portions. 7. A method according to claim 6, which can be easily divided in terms of contact of capsule parts. The method of claim 2, wherein the caplets contained in the capsule have preformed steps or grooves so that the solid dosage form can be divided into separate portions. The method of claim 6, wherein the caplets contained in the capsule are coated or uncoated with a coating that is acceptable for tablet processing. The method of claim 1, wherein the adhesive is sprayed onto the surface of the caplet and / or the inner surface of the capsule portions immediately prior to assembly. The method of claim 33, wherein the adhesive is a solution of tackidex or gelatin. The method of claim 1, wherein the caplet included in the capsule comprises a pharmaceutically active composition. The method of claim 1, wherein the caplets included in the capsule comprise an agrochemically active composition. The method of claim 1, wherein the caplet contained in the capsule comprises a foodstuff composition. The method of claim 1, wherein the caplets contained in the capsule comprise a dye composition. The method of claim 35, wherein the caplets contained in the capsule are betamethasone, thioctic acid, sotalol, salbutamol, norphenephrine, silymarin, dihydroergotamine, buflomedil, etofibrate, indomethacin, Oxazepam, acetyldigitoxin, pyroxicam, haloperidol, isosorbide mononitrate, amitriptyline, diclofenac, nifedipine, verapamil, pyritinol, nitridipine, doxycycline, brominehexine, methylprednisolone, clonidine, fenofibrate , Allopurinol, pyrenzepine, levothyroxine, tamoxifen, methyldigoxin, o- (β-hydroxyethyl) -rutoside, propicillin, acyclovirmonitrate, paracetamolol, naphthydrofuryl, pentoxifylline, Propafenone, acebutolol, 1-thyroxine, tramadol, bromocriptine, loperamide, ketopinene, phenoterol, ca-dobesylate, propranolol, minocycline, nisergoline, ambroxol, memetholone Prolol, β-Sitosterin, Enalapril Hydrogenmaleate, Bezafibrate, Isosorbide Dinitrate, Gallopamil, Xanthinol Nicotinate, Digitoxin, Flunitrazepam, Bencyclane, Despanthenol, Pindolol, lorazepam, diltiazem, piracetam, phenoxymethylpenicillin, furosemide, bromazepam, flunarizine, erythromycin, metoclopramide, acetamecin, ranitidine, biferidene, metamizol , Doxepin, dipotassium-chlorasepart, tetrazepam, esturamustine phosphate, terbutaline, captopril, mapproline, prazosin, atenolol, glybenclamide, cefachlor, ethyllephrine, cimetidine , Theophylline, hydromorphone, ibuprofen, primidone, clovazam, oxaceprole, methoxyprogesterone, flecaineide, Mg-pyridoxal-5-phosphate glutamate, high mecromon, etophylline clofibrate, bean Min, Cinnarizine, Diazepam, Ketoprofen, Flufenticol, Molecidomin, Glyborneuride, Dimethindene, Melferon, Soquinolol, Dihydrocodeine, Chlomethiazole, Clemastine, Glysoxide, Kali Dinogenase, oxyphedrine, baclofen, carboxymethylcyscin, thioredoxin, betahistine, 1-tryptophan, myrtol, bromelain, prenylamine, salazulfopyridine, astemisol, sulfi Reed, bengerazide, dibenzepine, acetylsalicylic acid, myconazole, nystatin, ketoconazole, sodium picosulphate, cholestyramate, gemfibrozil, rifampin, fluorocortolone, mexyltine, amoxicillin, terpenadine, mucopolysaka Lid polysulfonic acid, triazolam, myanserine, thiapropeneaure, amezinium methylsulfate, mefloquine, probucol, quinidine, carbamazepine, Mg-1-aspartate, fenbutolol, pyretanide, Amitriptyline, Caprolone , Sodium valproate, mebeberine, bisacodeyl, 5-amino-salicylic acid, dihydralazine, magaldrate, phenprocomon, amantadine, naproxen, carteolol, pamotidine, methyldopa, auranopine, estri Allol, nadolol, levomepromazine, doxorubicin, medophenoxart, azathioprine, flutamide, norfloxacin, pendylin, prazimallium bitartrate, aescin, acromycin, anipamil, benzocaine , β-carotene, chloramphenicol, chlorodiazepoxide, chlormadinone acetate, chlorothiazide, cinnarizine, clonazepam, codeine, dexamethasone, dicoumarol, digoxin, drotaberine, gramicidine, griseopin, Hexobarbital hydrochlorothiazide, hydrocortisone, hydroflumethiazide, ketoprotene, ronetyl, medazepam, mepruside, methanedrostenolone, sulfaferrin, nalidic acid, nitrazepam, nitro Lantoin, estradiol, papaverine, phenacetin, phenobarbital, phenylbutazone, phenytoin, prednisone, reserpin, spironolactin, streptomycin, sulfamethazole, sulfamethazine, sulfamethoxazole, sulfamethoxydia A pharmaceutical composition with an active substance selected from the group consisting of xenon, sulfatiazole, sulfisoxazole, testosterone, tolazamide, tolbutamide, trimetaprim, tyrotricin or mixtures thereof. The method of claim 13, wherein the shell halves do not completely cover the caplet. 41. The method of claim 40, wherein the shell halves and caplets are different in color. 42. The method of claim 41 wherein the shell halves are the same color and the caplets are different in color. After the hollow capsules and caps or pre-assembled capsules have been produced, the moisture content of the capsule shells is maintained in a humid state with a relative humidity of about 40 to about 90% to about 14 to about 19 weight percent (about 16 to about 18 weight percent). Or re-humidify with the moisture content prior to feeding into the capsule charger, and keep the moisture inside the charger at the moisture content as described above during orientation adjustment and filling, and And maintaining the capsule cap in the same state until assembled, and drying the encapsulated formulation at a relative humidity of about 20 to about 40% and a temperature of about 15 to about 60 ° C. The method of claim 43, wherein the water content of the capsule shell is in the range of at least about 15% and less than about 16% by weight of the capsule shell weight. 44. The method of claim 43, wherein the encapsulated formulation is dried at a temperature in the range of about 15 to about 60 ° C. 46. The method of claim 45, wherein the encapsulated formulation is dried at a temperature in the range of about 18 to about 25 ° C.