RU2777558C2 - Improved pharmaceutical compositions - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: free-flowing pharmaceutical composition is proposed, containing (1) lyophilized granules containing one or several active ingredients, and (2) a composition of a mixture, containing sorbitol and vaseline oil, where the composition contains from 0.01% to 30% by weight of the active ingredient(s), from 70% to 99.99% by weight of the composition of a mixture, and from 0% to 29.99% by weight of other pharmaceutically acceptable excipients. At the same time, the composition of a mixture contains from 955 to 99.9% by weight of sorbitol, from 0.1% to 5% by weight of vaseline oil, and from 0% to 4% by weight of citric acid. A packaging containing the specified pharmaceutical composition, a method for the manufacture of the specified composition, and the use of a solid mixture containing sorbitol and vaseline oil in the specified amount for the manufacture of a pharmaceutical composition are also proposed.

EFFECT: obtained composition has improved properties of fluidity, moisture protection, antistatic properties, as well as high uniformity of anti-adhesive properties preventing adhesion.

16 cl, 17 dwg, 9 ex

Description

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions, to methods for their preparation and to their use for the treatment and prevention of diseases in mammals, in particular in humans.

STATE OF THE ART TO which THE INVENTION RELATES

Pharmaceutical dosage forms that dissolve rapidly when placed in the patient's mouth, thereby delivering the desired dose of pharmaceutically active substances, are particularly useful when the dosage form can be taken without water. Such dosage forms are generally preferred for children and the elderly, as well as for people with difficulty in swallowing and/or taking tablets or capsules.

Rapidly dissolving dosage forms are usually prepared using a multi-stage process. Some of these processes use a lyophilization step during which the solvent is removed from the solution and/or suspension containing the pharmaceutically active substance, the carrier material and the solvent.

Pharmaceutical formulations made by lyophilization have various advantages as well as various problems such as problems of free flow, moisture absorption, bitter taste, dose uniformity and content uniformity. The present invention aims to overcome these problems.

SUMMARY OF THE INVENTION

The present invention relates to a new composition of a mixture of sorbitol and liquid paraffin for use in improving the properties of pharmaceutical formulations in several ways, i. flow properties, moisture protection, antistatic properties and compressibility (Carr index). The mixture composition may also contain citric acid and has the ability to soften the taste of bitter medicines.

Thus, the present invention relates to a free-flowing solid pharmaceutical composition containing one or more active ingredients and a mixture composition containing or consisting of sorbitol, liquid paraffin and optionally citric acid.

In addition, the present invention relates to a mixture containing or consisting of sorbitol, paraffin oil and optionally citric acid, for use in the manufacture of a pharmaceutical composition containing one or more active ingredients.

The present invention also relates to methods for the manufacture of a solid pharmaceutical composition according to the invention, including:

(a) obtaining a lyophilized powder by sublimation of a solvent from a preparation containing one or more active ingredients and a solvent;

(b) obtaining a mixture composition containing or consisting of sorbitol, liquid paraffin and optionally citric acid;

(c) mixing the mixture composition obtained in step (b) with the lyophilized powder obtained in step (a).

BLUEPRINTS

Figure 1 compares the compressibility index (Carr index) of the compositions according to example 1 and comparative examples A-E.

Figure 2 compares the Hausner ratio for the compositions according to example 1 and comparative examples A-E.

Figure 3 shows the % moisture content of the compositions according to example 1 and comparative examples A-E, depending on the storage time.

Figure 4 compares the % residual content of the compositions according to example 1 and comparative examples A-E.

Figure 5 shows a photograph of the stick-pack according to the invention.

Figure 6 compares the compressibility index (Carr index) of the compositions according to example 2 and comparative examples F-K.

Figure 7 compares the Hausner ratio for the compositions according to example 2 and comparative examples F-K.

Figure 8 shows the % moisture content of the compositions according to example 2 and comparative examples F-K, depending on the storage time.

Figure 9 compares the % residual content of the compositions according to example 2 and comparative examples F-K.

Figure 9 compares the % residual content of the compositions according to example 2 and comparative examples F-K.

FIG. 10 compares the compressibility index (Carr index) of the formulations of Examples 3-4 and Comparative Examples L-Q.

Figure 11 compares the Hausner ratio for the compositions according to examples 3-4 and comparative examples L-Q.

Figure 12 shows the % moisture content of the compositions according to examples 3-4 and comparative examples L-Q, depending on the storage time.

Figure 13 compares the % residual content of the formulations according to Examples 3-4 and Comparative Examples L-Q

FIG. 14 compares the compressibility index (Carr index) of the formulations according to Example 5 and Comparative Examples R-W.

FIG. 15 compares the Hausner ratio of the formulations according to Example 5 and Comparative Examples R-W.

16 shows the % moisture content of the formulations according to Example 5 and Comparative Examples R-W as a function of storage time.

17 compares the % residual content of the formulations according to Example 5 and Comparative Examples R-W.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a new composition of a mixture of sorbitol and liquid paraffin for use in improving the properties of pharmaceutical formulations in several ways, i. flow properties, moisture protection, antistatic properties and compressibility. The mixture composition may also contain citric acid and has the ability to soften the taste of bitter medicines.

The new blend, when mixed with the lyophilized powder, provides a pharmaceutical formulation with improved properties such as flow properties, moisture protection, antistatic properties and compressibility.

Thus, the present invention relates to a free-flowing solid pharmaceutical composition containing one or more active ingredients and a mixture composition containing or consisting of sorbitol, liquid paraffin and optionally citric acid.

The composition preferably contains from 0.01% to 30% by weight of one or more active ingredients, from 70% to 99.99% by weight of the mixture composition, and from 0% to 30% by weight of one or more other pharmaceutically acceptable excipients. More preferably, the composition contains from 0.1% to 28% by weight of one or more active ingredients, from 72% to 99.9% by weight of the mixture composition, and from 5% to 30% by weight of one or more other pharmaceutically acceptable excipients. . In one embodiment of the invention, the formulation is prepared by a process comprising the steps of preparing a formulation of the blend by mixing sorbitol, paraffin oil and optionally citric acid, and adding the formulation of the blend to the active ingredient(s), which is preferably a lyophilized powder.

In addition, the present invention relates to the composition of a mixture containing or consisting of sorbitol, liquid paraffin and optionally citric acid for use in the manufacture of a pharmaceutical composition containing one or more active ingredients. The mixture composition preferably contains from 95 to 99.9% by weight of sorbitol, from 0.1% to 5% by weight of liquid paraffin, and from 0 to 4% by weight of citric acid. More preferably, the mixture composition contains from 96 to 99.5% by weight of sorbitol, from 0.5% to 4% by weight of liquid paraffin, and from 0.5 to 2% by weight of citric acid. In one embodiment, the composition of the mixture consists of the indicated components in the indicated preferred and more preferred ratios.

Also, the present invention relates to a method for manufacturing a solid pharmaceutical composition according to the invention, including:

(a) obtaining a lyophilized powder by sublimation of a solvent from a preparation containing one or more active ingredients and a solvent;

(b) obtaining a mixture composition containing or consisting of sorbitol, liquid paraffin and optionally citric acid;

(c) mixing the mixture composition obtained in step (b) with the lyophilized powder obtained in step (a).

The process according to the invention makes it possible to obtain a solid pharmaceutical composition in the form of a free-flowing powder.

Preferred proportions of the active ingredient(s), sorbitol, liquid paraffin, citric acid and mixture composition in the method of the present invention are the same as in the pharmaceutical composition of the present invention.

The solvent used in the preparation to be lyophilized containing the active ingredient(s) and the solvent is usually water.

The terms "active ingredient" and "pharmaceutically active ingredient" are used interchangeably herein.

The pharmaceutical composition of the present invention contains one or more pharmaceutically active ingredients. They may be selected, for example, from oligopeptides, polypeptides (proteins), nucleotides, polynucleotides and "small molecular weight compounds". Non-limiting examples of pharmaceutically active ingredients that can be used in the present invention are pain relievers, alpha-blockers, antiallergic agents, antiasthma agents, antirhinitis agents, antiurticaria agents, anti-inflammatory agents, antiarrhythmic agents, antibacterial agents, antipsychotic agents, antidiabetic agents. , antidiuretics, antiepileptics, antifungals, antigout agents, antihypertensives, urinary incontinence agents, migraine agents, antimuscarinics and immunosuppressants, antiviral agents, anxiolytics, sedatives, hypnotics and neuroleptics, anti-benign hyperplasia agents (anti-BPH agents ), decongestants, diuretics, enzymes, antiparkinsonism agents, gastrointestinal agents, histamine receptor antagonists, antidepressants fetuses, endometriosis agents, hormone replacement therapy agents, lipid regulators, local anesthetics, neuromuscular agents, motion sickness agents, nutrients, oral vaccines, proteins, peptides and recombinant drugs, proton pump inhibitors, anti-schizophrenia agents, hormones, contraceptives, anti-seizure/panic disorders, anti-sexual dysfunction (male and female), etc.

Specific non-limiting examples of these active ingredients are:

Antiallergic drugs: desloratidin, loratidin, montelukast, montelukast sodium, cetirizine, fexofenadine, ebastine.

Alpha blockers: tamsulosin, silodosin.

Painkillers and anti-inflammatory drugs: aspirin, aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flubiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozine, phenyloxybutazone, phenyloxybutazone, phenyloxybutazone, phenyloxybutazone, sulindac, paracetamol.

Antiarrhythmic agents: amiodarone HCl, disopyramide, flecyanide acetate, quinidine sulfate.

Antibacterials: benetamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, clooxycillin, demeclocycline, doxycillin, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetazol, sulfacetazine, sulfapyridine, tetracycline, trimethoprim.

Antipsychotics: amoxapine, cyclazindol, maprotiline HCl, mianserin HCl, nortriptyline HCl, trazodone HCl, triimipramine maleate.

Antidiabetic agents: acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.

Antidiuretics: desmopressin and its analogue, desmopressin acetate.

Antiepileptics: beclomid, carbamazepine, clonezepam, etotoin, methoin, metsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, fensuximide, primidone, sultiam, valproic acid.

Antifungals: amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosin, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, terconazole, thioconazole, undecenoic acid.

Antigout drugs: allopurinol, probenecid, sulfinpyrazone.

Antihypertensive agents: amlodipine, benidipine, darodipine, diltiazem HCl, diazoxide, felodipine, guanabenza acetate, indoramine, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine, terazosin HCl.

Anti-migraine agents: rizatriptan, dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate, caffeine.

Antimuscarinics: oxybutynin, tolterodine, atropine, benzhexol HCl, biperiden, etopropazine HCl, hyoscine butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine, oxyphencyclimine HCl, tropicamide.

Anti-rhinitis, anti-urticaria: cetrizine, fexofenadine, ebastine, loratidine, montelukast.

Antivirals: acyclovir, amantadine hydrochloride, famiciclovir, zidovadine, didanosine, zalcitabine, foscarnet sodium.

Anxiolytics, sedatives, hypnotics and neuroleptics: alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlorpheniramine, chlormethiazol, chlorpromazine, clobazam, clonazepane, clothiazepam, clozapine, etynadropidol , флунанизон, флунитразепам, флуопромазин, флупентиксола деканоат, флуфеназина деканоат, флуразепам, галоперидол, лоразепам, лорметазепам, медазепам, мепробамат, метаквалон, мидазолам, нитразепам, оксазепам, пентобарбитон, перфеназин фенилэфрин, пимозид, прохлорперазин, псевдоэфедрин HCL, сульпирид, темазепам, тиоридазин , triazolam, zopiclone.

Contraceptives: clomiphene citrate, danazol, desogestrel, ethinyl estradiol, ethindiol, ethyndiol diacetate, levonorgesterel, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norethisterone enanthate, norgestrel, estradiol, conjugated estrogens, dihydrogesterone, progesterone, stanozolol, stilboestrol.

Decongestants: pseudoephedrine hydrochloride.

Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide, chlorthiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.

Enzymes: pancreatin, pepsin, lipase.

Epilepsy: gabapentin

Anti-parkinsonism agents: bromocriptine mesylate, lisuride maleate, selegiline, para-fluoroselegiline, lazabemide, rasagiline, 2-BUMP [N-(2-butyl)-N-methylpropargylamine], M-2-PP [N-methyl-N-( 2-pentyl)-propargylamine], MDL-72145 [beta-(fluoromethylene)-3,4-dimethoxybenzenethanamine], mofegiline, apomorphine, N-propylnoraporfin, cabergoline, metergoline, naxagolide, pergolide, piribedil, ropinirole, terguride, quinagolide .

Gastrointestinal agents: bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, metoclopramide, famotidine, loperamide, mesalazine, nizatidine, esomeprazole, metopimazine, pantoprazole, ondansetron HCl, granisetron, tropisetron, dolasetron, ranitidine HCl, sulfasalazine, lansoprazole.

Histamine receptor antagonists: acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate, flunarizine HCl, loratidine, meclozine HCl, oxatomide, terfenadine, triprolidine.

Hormones: agonists or antagonists of human growth hormone (HGH), follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), nafarelin, triptorelin, cetrorelix, atosiban.

Means of hormone replacement therapy: dihydrogesterone.

Antihypertensive drugs: enalapril.

Means for lactation: oxytocin, oxytocin agonists.

Lipid-regulating agents: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

Local anesthetics: amethocaine, amylocaine, benzocaine, bucrocaine, bupivacaine, butacaine, butanylicaine, butoxycaine, butylaminobenzoate, karticaine, chlorprocaine, cinchocaine, clibucaine, clormecaine, coca, cacaine, cyclomethicaine, dimethisoquine, diperbenzodone, diclocaine, ethyl p-acetylamiperidine, ethyl p-acetyl chloride ethidocaine, hexylcaine, isobutamben, ketocaine, lignocaine, mepivacaine, meprilcaine, mirtecaine, octacaine, oxetazaine, oxybuprocaine, parethoxycaine, pramoxine, prilocaine, procaine, propranocaine, propoxycaine, proxymetacaine, ropivacaine, tolicaine, tricaine, trimecaine, vadocaine.

Anti-motion sickness: diphenhydramine.

Neuromuscular agents: pyridostigmine.

Non-steroidal antiandrogens: enzalutamide.

Nutrients: beta-carotene, vitamins such as vitamin A, vitamin B ₂ , vitamin D, vitamin E, vitamin K, minerals.

Oral vaccines: to prevent or reduce symptoms of diseases such as influenza, tuberculosis, meningitis, hepatitis, whooping cough, polio, tetanus, diphtheria, malaria, cholera, herpes, typhoid, HIV, AIDS, measles, Lyme disease, traveler's diarrhea, hepatitis A , B and C, otitis media, dengue fever, rabies, parainfluenza, rubella, yellow fever, dysentery, legionnaires' disease, toxoplasmosis, Q-fever, hemorrhagic fever, Argentine hemorrhagic fever, caries, Chagas disease, urinary tract infections due to E coli , pneumococcal disease, mumps, chikungunya, hay fever, asthma, rheumatoid arthritis, carcinomas, coccidosis, Newcastle disease, enzootic pneumonia, feline leukemia, atrophic rhinitis, erysipelas, foot-and-mouth disease and swine pneumonia, or to prevent or reduce the symptoms of diseases, caused by Vibrio spp., Salmonella spp., Bordetella spp., Haemophilus spp., Toxoplasmosis gondii , cytomegalovirus, Chlamydia spp., in streptococci, Norwalk virus, Escherischia coli , Helicobacter pylori , rotavirus, Neisseria gonorrhae , Neisseria meningiditis , adenovirus, Epstein-Barr virus, Japanese encephalitis virus, Pneumocystis carini , Herpes simplex , Clostridia species, respiratory syncytial virus, Klebsiella species, Shigella species , Pseudomonas aeruginosa , parvovirus, Campylobacter spp., Rickettsia spp., Varicella zoster , Yersinia spp., Ross river virus, JC virus, Rhodococcus equi , Moraxella catarrhalis , Borrelia burgdorferi and Pasteurella haemolytica , BCG.

Drugs against urinary dysfunction: tamsulosin, trospium chloride, tolterodine, oxybutynin, solifenacin.

Proteins, peptides and recombinant drugs: recombinant hormones and isohormones, recombinant cytokines, recombinant plasminogens, TNF receptor fusion protein, monoclonal antibodies, nucleic acids, antisense oligonucleotides, oligonucleotides, glycoproteins and adhesion molecules, calcitonin, octreotide, insulin and insulin analogs, etanercept , pegfilgrastim, liraglutide, bivalirudin, nesiritide, ceruletide, bantiromide, exenatide, gonadorelin, enfuvirtide, vancomycin, icatibant, secretin, leuprolide, recombinant glucagon, oxytocin, sermorelin, gramicidin D, recombinant insulin, capreomycin, vasopressin, cosinotropin, bacitratropin, vapreotide, thymalfasin, mecasermin, teriparatide, corticotropin, pramlitinide.

Phosphate binders: sevelamer.

Drugs against sexual dysfunction: cabergoline, oxytocin, tadalafil, sildenafil, vardenafil.

Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine.

In a particular embodiment, the active ingredient of the formulation of the invention is selected from the group consisting of desloratidine, montelukast, solifenacin, silodosin, sildenafil, and any pharmaceutically acceptable salt thereof.

In a specific embodiment, the active ingredient of the formulation of the invention is desloratidine.

In a specific embodiment, the active ingredient of the formulation of the invention is sildenafil.

In a specific embodiment, the active ingredient of the formulation of the invention is solifenacin.

In addition to the components described above, the composition may also include other excipients (auxiliaries, additional substances), such as, but not limited to, fillers, thickeners (including, but not limited to, guar gum and xanthan gum), binders, diluents, lubricants, pH adjusters, protectants, viscosity enhancers, moisture enhancers, non-effervescent leavening agents, effervescent leavening agents, surfactants, antioxidants, wetting agents, coloring agents, flavoring agents, taste masking agents, sweeteners, preservatives etc.

A suitable route of administration for the dosage form of the present invention is oral administration.

In one embodiment, the pharmaceutical composition of the invention may be administered to a patient in powder form.

In another aspect, the pharmaceutical composition of the invention is in a single dose dispensing package of the composition, also referred to as a unit dosage form. Non-limiting examples of packaging/unit dosage form are sachets and stick packs.

In another embodiment, the pharmaceutical composition of the invention, for example in the form of a powder, is packaged in a multiple dosage form, i. e. dosage form, allowing the selection of multiple doses of arbitrary size. Non-limiting examples of multiple dosage forms are a bottle and any other container capable of containing a powder.

A patient who takes a formulation in a free-flowing form can be sure that he is receiving the entire dosage, i.e. there will be no residue left in the package/single dosage form.

In one embodiment, oral administration is carried out by emptying the sachet, stick-pack or (any other) unit package containing the powder onto the tongue and swallowing the contents.

In another embodiment, oral administration is carried out by dissolving the powder in a solvent (eg, a glass of water) and then drinking the solution.

The precise dosage and mode of administration of the dosage form necessarily depend on the therapeutic effect desired to be achieved and may vary depending on the particular active ingredient, route of administration, age and condition of the particular individual to whom the formulation is intended to be administered. Occasionally, patients may be instructed to take two or any number of unit dosage forms, such as stick packs, in one administration, or only a portion, such as half or a quarter, of the unit dosage form in one administration.

The compositions of the invention are unique in that they have improved flow properties, moisture content, antistatic properties and compressibility.

The pharmaceutical composition according to the invention can be obtained by:

(a) obtaining a lyophilized powder by sublimation of a solvent (eg water), for example in a lyophilization process, from a preparation that contains the active ingredient(s) and a solvent;

(b) obtaining a mixture composition containing sorbitol and liquid paraffin. The mixture composition may optionally contain citric acid;

(c) mixing the mixture composition with the lyophilized powder obtained in step (a) to obtain a pharmaceutical composition with improved flow properties, moisture protection, antistatic properties and compressibility.

According to one embodiment, the resulting free flowing composition is in a stick pack.

According to another embodiment, the resulting free flowing composition is in a sachet.

The free-flowing sorbitol/Vaseline oil mixture composition is mixed with the lyophilized powder by methods known in the art, such as geometric mixing or mixing using any type of blender.

EXAMPLES

The invention is further described in the following examples, which are not intended to limit the scope of the claimed invention.

Materials and methods

Material Manufacturer Provider Polacrillin potassium (resin) Dow France S.A.S. Colorcon India Maltodextrin Roquette France SignetIndia Lemon acid Merck Merck Talc Imerys Talc SignetIndia magnesium stearate sunshine sunshine Vaseline oil Ashwini chemicals pvt. Ltd. Ashwini chemicals pvt. Ltd. Sorbitol Roquette SignetIndia Desloratidin Enaltec Enaltec Sodium hydroxide Merck Merck Mannitol Roquette France SignetIndia Hydroxypropylcellulose L Granules of tartaric acid ideal cures ideal cures Sildenafil citrate Rakshit medicines Rakshit medicines Solifenacin MSN Lab MSN Lab

Example 1 Placebo Formulation

The composition (placebo) was obtained using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Resin 20.0 2 Maltodextrin 77.0 3 Lemon acid 3.0 four Water q.s. up to 400 g Mixture composition 5 Sorbitol 394.5 6 Lemon acid 3.0 7 Vaseline oil 2.5

Manufacturing method:

I. Lyophilized granules

1. Citric acid was dissolved in 200 g of water using a magnetic/overhead stirrer for 5 minutes.

2. Added resin with continuous stirring and the resulting dispersion was continued to stir for 1 hour.

3. Added maltodextrin with continuous stirring.

4. The final weight of the solution/dispersion was adjusted to 400 g using purified water.

5. Stirring of the solution/dispersion was continued for 10 minutes using a magnetic/overhead stirrer.

6. This solution/dispersion was filled into a stainless steel tray and lyophilized in a lyophilizer.

7. After lyophilization was completed, the lyophilized cake was sieved through a #40 sieve to obtain lyophilized granules.

II. Mixture composition

8. Sorbitol was passed through a #40 sieve and mixed with crushed and sieved citric acid in a two-cone drum mixer for 2 minutes at 10 rpm.

9. Vaseline oil was added dropwise to 40 g of the mixture of step 8 and mixed by hand to obtain a homogeneously distributed composition of the mixture.

10. The blend composition was sifted through a #60 sieve and then mixed with the remaining blend from step 8 using a double cone mixer for 3 minutes at 10 rpm to obtain the final blend formulation.

III. Compound

11. The lyophilized granules from step 7 were mixed with the final blend composition from step 10 in a two-cone drum mixer for 5 minutes at 10 rpm to obtain a free-flowing composition (placebo).

12. The free-flowing composition was filled into stick packs and sealed, at a rate of 500 mg per stick pack (see Figure 5).

Example 2 Desloratidine Composition

The composition of desloratidine was prepared using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Desloratidin 10.0 2 Resin 20.0 3 Maltodextrin 67.0 four Lemon acid 3.0 5 Water q.s. up to 400 g Mixture composition 6 Sorbitol 394.5 7 Lemon acid 3.0 eight Vaseline oil 2.5

Manufacturing technique

I. Lyophilized granules

1. Citric acid was dissolved in 200 g of water using a magnetic/overhead stirrer for 5 minutes.

2. Desloratidine was added with continuous stirring using a magnetic/overhead stirrer.

3. Added the resin with continuous stirring and the resulting dispersion continued to stir for 1 hour.

4. Added maltodextrin with continuous stirring.

5. The final weight of the solution/dispersion was adjusted to 400 g using purified water.

6. Stirring of the solution/dispersion was continued for 10 minutes using a magnetic/overhead stirrer.

7. This solution/dispersion was filled into a stainless steel tray and lyophilized in a lyophilizer.

8. After lyophilization was completed, the lyophilized cake was sieved through a #40 sieve to obtain lyophilized granules.

II. Mixture composition

9. Sorbitol was passed through a #40 sieve and mixed with crushed and sieved citric acid in a two-cone drum mixer for 2 minutes at 10 rpm.

10. Vaseline oil was added dropwise to 40 g of the mixture from step 9 and mixed by hand to obtain a uniformly distributed mixture composition.

11. The blend composition was sifted through a #60 sieve and then mixed with the rest of the blend from step 9 using a double cone mixer for 3 minutes at 10 rpm to obtain the final blend formulation.

III. Compound

12. The lyophilized granules from step 8 were mixed with the final blend composition from step 11 in a two-cone drum mixer for 5 minutes at 10 rpm to obtain a free-flowing formulation of desloratidine.

13. The free-flowing composition was filled into stick packs and sealed, at a rate of 500 mg per stick pack (see FIG. 5).

Comparative example A

The composition of the granules was obtained essentially as described in example 1, using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) one Resin 33.0 2 Maltodextrin 129.0 3 Lemon acid 8.0 four Water q.s. up to 200 g

Comparative example B

A comparative pharmaceutical formulation was prepared essentially as described in Example 1 using a mixture formulation containing talc and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Resin 33.0 2 Maltodextrin 127.0 3 Lemon acid 5.0 four Water q.s. up to 200 g Mixture composition 5 Lemon acid 3.0 6 Talc 2.5

Comparative Example C

A comparative pharmaceutical formulation was prepared essentially as described in Example 1 using a blend formulation containing magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Resin 33.0 2 Maltodextrin 127.0 3 Lemon acid 5.0 four Water q.s. up to 200 g Mixture composition 5 Lemon acid 3.0 6 magnesium stearate 2.5

Comparative example D

A comparative pharmaceutical formulation was prepared essentially as described in Example 1 using a blend formulation containing talc, magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Resin 33.0 2 Maltodextrin 127.0 3 Lemon acid 5.0 four Water q.s. up to 200 g Mixture composition 5 Lemon acid 3.0 6 Talc 1.3 7 magnesium stearate 1.3

Comparative example E

A comparative pharmaceutical formulation was prepared essentially as described in Example 1 using a mixture formulation containing only paraffin oil and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Resin 33.0 2 Maltodextrin 127.0 3 Lemon acid 5.0 four Water q.s. up to 200 g Mixture composition 5 Lemon acid 3.0 6 Vaseline oil 2.5

Comparative example F

The composition of the granules was obtained essentially as described in example 2, using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) one Desloratidin 16.7 2 Resin 33.40 3 Maltodextrin 111.89 four Lemon acid 8.0 5 Water q.s. up to 668 g

Comparative example G

A comparative pharmaceutical formulation was prepared essentially as described in Example 2 using a mixture formulation containing talc and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Desloratidin 16.45 2 Resin 33.0 3 Maltodextrin 110.0 four Lemon acid 5.0 5 Water q.s. up to 658 g Mixture composition 6 Lemon acid 3.0 7 Talc 2.5

Comparative example H

A comparative pharmaceutical formulation was prepared essentially as described in Example 2 using a blend formulation containing magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Desloratidin 16.45 2 Resin 33.0 3 Maltodextrin 110.0 four Lemon acid 5.0 5 Water q.s. up to 658 g Mixture composition 6 Lemon acid 3.0 7 magnesium stearate 2.5

Comparative Example I

A comparative pharmaceutical formulation was prepared essentially as described in Example 2 using a blend formulation containing talc, magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Desloratidin 16.45 2 Resin 33.0 3 Maltodextrin 110.0 four Lemon acid 5.0 5 Water q.s. up to 658 mg Mixture composition 6 Lemon acid 3.0 7 Talc 1.3 eight magnesium stearate 1.3

Comparative example J

A comparative pharmaceutical formulation was prepared essentially as described in Example 2 using a mixture formulation containing only paraffin oil and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Desloratidin 16.45 2 Resin 33.0 3 Maltodextrin 127.0 four Lemon acid 5.0 5 Water q.s. up to 200 g Mixture composition 6 Lemon acid 3.0 7 Vaseline oil 2.5

Comparative example K

A comparative pharmaceutical formulation was prepared essentially as described in Example 2 using a mixture formulation containing only sorbitol and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Desloratidin 10.0 2 Resin 20.0 3 Maltodextrin 67.0 four Lemon acid 3.0 5 Water q.s. up to 400 g Mixture composition 6 Sorbitol 400.0

Example 3 Sildenafil Composition

Sildenafil formulation was prepared using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Sorbitol 604.87 7 Lemon acid 64.63 eight Vaseline oil 3.0

Manufacturing technique

I. Lyophilized granules

1. Sodium hydroxide was dissolved in 370 ml of purified water while stirring using an overhead stirrer for 10 minutes at 1000 rpm.

2. Sildenafil citrate was dispersed uniformly in the step 1 solution with stirring for 30 minutes.

3. The dispersion obtained in step 2 was homogenized at 10,000 rpm for 60 minutes using a homogenizer and an overhead stirrer.

4. Hydroxypropyl cellulose L was dissolved in water (166.5 g) and the solution was added to the dispersion stage 2 with stirring.

5. Mannitol was added to the dispersion.

6. The final weight of the solution/dispersion was adjusted to 1000 g using purified water.

7. Stirring of the solution/dispersion was continued for 10 minutes using a magnetic/overhead stirrer.

8. This solution/dispersion was filled into a stainless steel tray and lyophilized in a lyophilizer.

9. After lyophilization was completed, the lyophilized cake was sieved through a #40 sieve to obtain lyophilized granules.

II. Mixture composition

10. Sorbitol was passed through a #40 sieve and mixed with ground and sieved citric acid in a two-cone drum mixer for 2 minutes at 10 rpm.

11. Vaseline oil was added dropwise to 40 g of the mixture of step 10, and mixed by hand to obtain a uniformly distributed composition of the mixture.

12. The blend composition was sieved through a #60 sieve and then mixed with the rest of the blend from step 9 using a double cone mixer for 3 minutes at 10 rpm to obtain the final blend formulation.

III. Compound

13. The lyophilized granules from step 9 were mixed with the final blend composition from step 12 in a two-cone drum mixer for 5 minutes at 10 rpm to obtain a free-flowing formulation of sildenafil citrate.

14. The free-flowing formulation was filled into stick packs and sealed, at 500 or 1000 mg per stick pack (see FIG. 5).

Example 4 Sildenafil Composition

Sildenafil formulation was prepared essentially as described in Example 3 using the following ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Sorbitol 604.87 7 Granules of tartaric acid 64.63 eight Vaseline oil 3.00

Comparative example L

The composition of the granules was obtained essentially as described in example 3 using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g

Comparative example M

A comparative pharmaceutical formulation was prepared essentially as described in Example 3 using a mixture formulation containing talc and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Lemon acid 64.63 7 Talc 3.0

Comparative example N

A comparative pharmaceutical formulation was prepared essentially as described in Example 3 using a blend formulation containing magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Lemon acid 64.63 7 magnesium stearate 3.0

Comparative example O

A comparative pharmaceutical formulation was prepared essentially as described in Example 3 using a blend formulation containing talc, magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Lemon acid 64.63 7 Talc 1.50 eight magnesium stearate 1.50

Comparative example P

Comparative pharmaceutical composition was prepared essentially as described in example 3, using a mixture composition containing liquid paraffin and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Lemon acid 64.63 7 Vaseline oil 3.0

Comparative example Q

A comparative pharmaceutical formulation was prepared essentially as described in Example 3 using a mixture formulation containing sorbitol and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Sildenafil citrate 140.48 2 Sodium hydroxide 30.12 3 Mannitol 149.45 four HPC-L 4.0 5 Purified water q.s up to 1000 g Mixture composition 6 Sorbitol 604.87

Example 5 Solifenacin Composition

The composition of solifenacin was prepared using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Solifenacin 10.0 2 Polacrillin potassium (resin) 20.0 3 Maltodextrin 67.0 four Lemon acid 3.0 5 Water q.s. up to 400 g Mixture composition 6 Sorbitol 394.5 7 Lemon acid 3.0 eight Vaseline oil 2.5

Manufacturing technique

I. Lyophilized granules

1. Solifenacin was dissolved in 140 g of water using a magnetic/overhead stirrer for 5 minutes.

2. Citric acid was added with continuous stirring using a magnetic/overhead stirrer.

3. Added the resin with continuous stirring and the resulting dispersion continued to stir for 1 hour.

4. Maltodextrin was dissolved in 140 g of water in a separate beaker, and then added to the mixture of stage 3 with continuous stirring.

5. The final weight of the solution/dispersion was adjusted to 400 g using purified water.

6. Stirring of the solution/dispersion was continued for 10 minutes using a magnetic/overhead stirrer.

7. This solution/dispersion was filled into a stainless steel tray and lyophilized in a lyophilizer.

8. After lyophilization was completed, the lyophilized cake was sieved through a #40 sieve to obtain lyophilized granules.

II. Mixture composition

9. Sorbitol was passed through a #40 sieve and mixed with crushed and sieved citric acid in a two-cone drum mixer for 2 minutes at 10 rpm.

10. Vaseline oil was added dropwise to 40 g of the mixture of step 9 and mixed by hand to obtain a uniformly distributed composition of the mixture.

11. The blend composition was sifted through a #60 sieve and then mixed with the rest of the blend from step 9 using a double cone mixer for 3 minutes at 10 rpm to obtain the final blend formulation.

III. Compound

12. The lyophilized granules from step 8 were mixed with the final blend composition from step 11 in a two-cone drum mixer for 5 minutes at 10 rpm to obtain a free-flowing solifenacin formulation.

13. The free-flowing composition was filled into stick packs and sealed, at a rate of 500 mg per stick pack (see FIG. 5).

Comparative example R

The composition of the granules was obtained essentially as described in example 5, using the following ingredients:

Ingredients Quantity per 1000 stick packs (g) one Solifenacin 16.5 2 Polacrillin potassium (resin) 33.0 3 Maltodextrin 110.5 four Lemon acid 5.0 5 Water q.s. up to 682 g

Comparative example S

A comparative pharmaceutical formulation was prepared essentially as described in Example 5 using a mixture formulation containing talc and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Solifenacin 16.5 2 Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 four Lemon acid 5.0 5 Water q.s. up to 682 g Mixture composition 6 Lemon acid 3.0 7 Talc 2.5

Comparative example T

A comparative pharmaceutical formulation was prepared essentially as described in Example 5 using a blend formulation containing magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Solifenacin 16.5 2 Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 four Lemon acid 5.0 5 Water q.s. up to 682 g Mixture composition 6 Lemon acid 3.0 7 magnesium stearate 2.5

Comparative example U

A comparative pharmaceutical formulation was prepared essentially as described in Example 5 using a blend formulation containing talc, magnesium stearate and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Solifenacin 16.5 2 Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 four Lemon acid 5.0 5 Water q.s. up to 682 g Mixture composition 6 Lemon acid 3.0 7 Talc 1.3 eight magnesium stearate 1.3

Comparative Example V

Comparative pharmaceutical composition was prepared essentially as described in example 5, using a mixture composition containing liquid paraffin and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Solifenacin 16.5 2 Polacrillin Potassium (Resin) 33.0 3 Maltodextrin 110.5 four Lemon acid 5.0 5 Water q.s. up to 682 g Mixture composition 6 Lemon acid 3.0 7 Vaseline oil 2.5

Comparative example W

A comparative pharmaceutical formulation was prepared essentially as described in Example 5 using a mixture formulation containing sorbitol and the following other ingredients :

Ingredients Quantity per 1000 stick packs (g) Freeze-dried granules obtained from a liquid composition consisting of: one Solifenacin 10.0 2 Polacrillin Potassium (Resin) 20.0 3 Maltodextrin 67.0 four Lemon acid 3.0 5 Water q.s. up to 400 g Mixture composition 6 Sorbitol 400.0

Example 6 Bulk Density and Bulk Density Test Results

Bulk and bulk density are important for understanding the flow properties of formulations. The bulk density of a material is the ratio of mass to volume (including the volume of voids between particles) of a powder sample of an uncompacted powder sample. Bulk density is the increased bulk density achieved after mechanically tapping the container containing the powder sample. Bulk density is determined by mechanically tapping the graduated cylinder containing the sample until further volume change is observed to be small. Since the interactions between particles that affect the bulk properties of a powder are also interactions that hinder the flow of a powder, a comparison of bulk and bulk density can provide a measure of the relative importance of these interactions in a given powder. Such a comparison is often used as a measure of the ability of a powder to flow, such as the compressibility factor or the Hausner ratio:

Compressibility index (Carr index):

Hausner relation:

,

,

V ₀ = apparent volume without compaction (total volume) V _f = final volume after compaction

The lower the values of the compressibility factor and the Hausner ratio, the better the flow properties of the powder.

Method for determining bulk density:

According to the method of the United States Pharmacopeia (USP) chapter <616>, method I, using a 100 ml cylinder with a division value of up to 1 ml and an amount of powder in which the apparent volume without compaction is between 50 and 100 ml.

Method for determining bulk density:

According to the United States Pharmacopeia (USP), chapter <616>, method I, with the following details:

- A 100-ml graduated cylinder (with divisions up to 1 ml) weighing 130 ± 16 g is placed on a stand weighing 240 ± 12 g.

- Carry out 10, 500 and 1250 taps on the powder sample and determine the corresponding volumes V ₁₀ , V ₅₀₀ and V ₁₂₅₀ to the nearest graduated unit.

- If the difference between V ₅₀₀ and V ₁₂₅₀ is less than or equal to 1 ml, then the bulk volume is equal to V ₁₂₅₀ .

- If the difference between V ₅₀₀ and V ₁₂₅₀ exceeds 1 ml, the measurement is repeated in steps such as 1250 taps until the difference between successive measurements is less than or equal to 1 ml.

Results:

Lineups Bulk density (g/ml) Bulk density (g/ml) Carr index Hausner ratio Example 1 0.476 0.652 26.984 1.370 Example 2 0.50 0.64 21.67 1.28 Comparative example A 0.192 0.333 42.308 1.733 Comparative example B 0.200 0.341 41.333 1.705 Comparative Example C 0.231 0.385 40,000 1.667 Comparative example D 0.208 0.366 43.056 1.756 Comparative example E 0.160 0.273 41.489 1.709 Comparative example F 0.24 0.37 33.87 1.51 Comparative example G 0.24 0.41 41.27 1.70 Comparative example H 0.27 0.39 30.91 1.45 Comparative Example I 0.26 0.39 34.48 1.53 Comparative example J 0.21 0.41 49.32 1.97 Comparative example K 0.44 0.63 29.41 1.42 Example 3 0.417 0.690 39.69 1.655 Example 4 0.444 0.714 37.77 1.607 Comparative example L 0.278 0.488 43.065 1.756 Comparative example M 0.308 0.541 43.07 1.757 Comparative example N 0.323 0.556 41.93 1.722 Comparative example O 0.323 0.541 40.32 1.676 Comparative example P 0.286 0.513 44.28 1.795 Comparative example Q 0.408 0.667 38.77 1.633 Example 5 0.429 0.667 35.714 1.556 Comparative example R 0.217 0.375 42.029 1.725 Comparative example S 0.224 0.395 43.284 1.763 Comparative example T 0.238 0.395 39.683 1.658 Comparative example U 0.238 0.395 39.683 1.658 Comparative Example V 0.188 0.375 50,000 2,000 Comparative example W 0.435 0.667 34.783 1.533

Example 7: Angle of repose:

The angle of repose is used to characterize the flow properties of solids. The angle of repose is a characteristic related to friction between particles or resistance to movement between particles. The natural spall angle is the constant three-dimensional angle (relative to the horizontal base) that a cone-like pile of material has.

Method (according to USP, general chapter <1174>) :

The angle of repose is formed on a fixed base with a retaining ledge to hold the powder layer on the base. The base must be free from vibration. The height of the funnel is changed to carefully form a symmetrical cone of powder. Care should be taken that there is no vibration as the funnel moves. The height of the funnel should be maintained approximately 2-4 cm from the top of the pile of powder as it forms, to minimize the effect of the falling powder on the top of the cone. If a symmetrical powder cone cannot be successfully and reproducibly formed, this method is not suitable. The angle of repose is determined by taking the height of the powder cone and calculating the angle of repose (a) using the following equation:

tan (a) = height / 0.5 base.

Results:

Lineups Angle of repose
(degree) Yield behavior Example 1 34 Good Example 2 36.66 not bad Comparative example A These formulations did not pass through the funnel due to pocketing and poor flow properties and thus could not be analyzed. Comparative example B Comparative Example C Comparative example D Comparative example E Comparative example F Comparative example G Comparative example H Comparative Example I Comparative Example J Comparative example K 41.10 Low Example 3 34 Good Example 4 35 good Comparative example L 37 Not bad Comparative example M These formulations did not pass through the funnel due to pocketing and poor flow properties and thus could not be analyzed. Comparative example N Comparative example O 36 Not bad Comparative example P These formulations did not pass through the funnel due to pocketing and poor flow properties and thus could not be analyzed. Comparative example Q 32 Good Example 5 31 Good Comparative example R 36 Not bad Comparative example S These formulations did not pass through the funnel due to pocketing and poor flow properties and thus could not be analyzed. Comparative example T 36 Not bad Comparative example U 37 Not bad Comparative Example V These formulations did not pass through the funnel due to pocketing and poor flow properties and thus could not be analyzed. Comparative example W 35 Good

Example 8: Moisture content:

Pharmaceutical formulations were placed on open Petri dishes, which were then placed in Climacel maintained at 25ºC/75% RH to simulate exposure to high humidity. The moisture content of each formulation was analyzed after 1, 2 and 6 hours in Climacel. Moisture content was evaluated using USP General Chapter 921 - Method for Determining Water Content.

Results:

Lineups Moisture contents
(wt%) Initially 1 hour 2 hours 6 hours Example 1 1.19 2.27 3.65 6.82 Example 2 1.49 3.08 5.80 7.88 Comparative example A 4.24 5.33 8.10 12.49 Comparative example B 4.40 5.12 8.31 13.11 Comparative Example C 4.57 5.77 6.98 13.28 Comparative example D 4.11 5.45 8.67 14.54 Comparative example E 4.34 5.48 7.96 13.64 Comparative example F 5.30 6.97 10.60 14.54 Comparative example G 5.31 8.16 11.65 15.23 Comparative example H 4.95 7.77 9.96 14.11 Comparative Example I 5.10 7.91 9.78 14.23 Comparative example J 6.32 9.00 10.92 14.57 Comparative example K 1.66 4.60 5.86 9.77 Example 3 2.1 3.01 4.45 10.95 Example 4 2.09 2.89 4.68 11.39 Comparative example L 4.73 6.72 9.12 14.24 Comparative example M 4.08 5.94 7.57 12.92 Comparative example N 4.07 6.69 7.9 12.75 Comparative example O 4.1 5.83 8.26 13.43 Comparative example P 4.03 6.54 8.54 13.41 Comparative example Q 2.05 3.2 4.86 12.06 Example 5 1.17 2.98 3.8 5.65 Comparative example R 4.65 10.19 14.64 13 Comparative example S 4.46 13.56 10.87 13.26 Comparative example T 4.14 10.24 10.11 13.42 Comparative example U 4.62 14.82 8.59 10.14 Comparative Example V 4.95 12.68 8.58 12.42 Comparative example W 1.94 2.49 3.11 8.37

Example 9 Tack Reducing Properties

The tack reducing properties of the composition were determined by determining the residual content using the following methodology:

Methodology:

The pharmaceutical formulations were uniformly filled into 10 flexible laminated stick packs as shown in FIG. The weight of the contents of each stick pack was recorded for further comparison. The filled stick bags were closed using a sealer. The sealed stick packs were held on a vibrating shear for 30 minutes to place the formulations in the corners of the stick pack. Each stick pack was opened by slitting one sealed side. The formulation from each stick pack was removed and weighed on a calibrated scale to determine the amount of formulation recovered from each stick pack. The residual content was calculated using the following formula:

(Stick pack fill weight) - (contents extracted from the stick pack) = Residual content

results

Lineups % residual content Standard deviation Example 1 2.04 0.39 Example 2 1.35 0.35 Comparative example A 6.49 1.14 Comparative example B 4.98 0.99 Comparative Example C 7.39 0.73 Comparative example D 5.11 1.03 Comparative example E 4.10 0.99 Comparative example F 4.76 0.80 Comparative example G 4.75 0.91 Comparative example H 4.02 0.56 Comparative Example I 4.04 0.34 Comparative example J 3.02 2.20 Comparative example K 1.94 0.50 Example 3 0.63 0.11 Example 4 0.6 0.11 Comparative example L 2.28 0.86 Comparative example M 2.78 0.57 Comparative example N 2.08 0.43 Comparative example O 2.25 0.34 Comparative example P 1.42 0.65 Comparative example Q 0.96 0.20 Example 5 2.15 0.22 Comparative example R 4.72 1.22 Comparative example S 8.19 3.88 Comparative example T 10.65 4.50 Comparative example U 10.68 5.85 Comparative Example V * Wet mass with very low fluidity Comparative example W 4.73 3.09

Claims (20)

1. A free-flowing pharmaceutical composition containing (1) lyophilized granules containing one or more active ingredients and (2) a mixture composition containing sorbitol and liquid paraffin, where the composition contains from 0.01% to 30% by weight of the active ingredient (s) , from 70% to 99.99% by weight of the mixture composition and from 0% to 29.99% by weight of other pharmaceutically acceptable excipients, and the composition of the mixture contains from 95% to 99.9% by weight of sorbitol, from 0.1 to 5% by weight of vaseline oil and from 0% to 4% by weight of citric acid. 2. The composition according to claim 1, containing from 0.1% to 28% by weight of the active ingredient(s), from 72% to 99.9% by weight of the composition of the mixture and from 5% to 27.9% by weight of one or several other pharmaceutically acceptable excipients. 3. Composition according to claim 1 or 2, where the composition of the mixture contains from 96 to 99.5% by weight of sorbitol, from 0.5% to 4% by weight of liquid paraffin and from 0% to 2% by weight of citric acid. 4. Composition according to claim 1 or 2, wherein the mixture composition consists of 95 to 99.9% by weight of sorbitol, 0.1% to 5% by weight of liquid paraffin and 0 to 4% by weight of citric acid. 5. Composition according to claim 4, wherein the composition of the mixture consists of 96 to 99.5% by weight of sorbitol, from 0.5% to 4% by weight of paraffin oil and from 0% to 2% by weight of citric acid. 6. Composition according to any one of claims 1 to 5, wherein the active ingredient is selected from the group consisting of desloratidine, montelukast, solifenacin, silodosin, sildenafil and pharmaceutically acceptable salts of the above active ingredients, and desmopressin and desmopressin acetate. 7. Composition according to any one of claims 1 to 5, wherein the active ingredient is desloratidine or a pharmaceutically acceptable salt thereof. 8. Composition according to any one of claims 1 to 5, wherein the active ingredient is montelukast or a pharmaceutically acceptable salt thereof. 9. Composition according to any one of claims 1 to 5, wherein the active ingredient is silodosin or a pharmaceutically acceptable salt thereof. 10. Composition according to any one of claims 1 to 5, wherein the active ingredient is sildenafil or a pharmaceutically acceptable salt thereof. 11. Composition according to any one of claims 1 to 5, wherein the active ingredient is solifenacin or a pharmaceutically acceptable salt thereof. 12. Composition according to any one of claims 1 to 5, wherein the active ingredient is desmopressin or desmopressin acetate. 13. A package containing a composition according to any one of the preceding claims. 14. A package according to claim 13, selected from the group consisting of a sachet and a stick pack. 15. The use of a solid mixture containing from 95% to 99.9% by weight of sorbitol, from 0.1% to 5% by weight of vaseline oil and from 0% to 4% by weight of citric acid for the manufacture of a pharmaceutical composition defined in paragraph .one. 16. A method for manufacturing a pharmaceutical composition according to any one of claims 1 to 12, including: (a) obtaining a lyophilized powder by sublimation of a solvent from a preparation containing one or more active ingredients and a solvent; (b) obtaining a mixture composition containing or consisting of sorbitol, liquid paraffin and optionally citric acid; (c) mixing the mixture composition obtained in step (b) with the lyophilized powder obtained in step (a).

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