Advanced drug delivery system

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns an oral drug delivery system including biliquid foam containing continuous hydrophilic phase 1 to 20 wt %, pharmaceutically acceptable oil 70 to 98 wt % producing discontinuous phase. A slightly water-soluble drug 0.1 to 20 wt % is dissolved or dispersed in said pharmaceutically acceptable oil. The drug delivery system also contains biliquid foam with included surface-active substance 0.5 to 10 wt % to produce stable biliquid foam with all the amounts specified in percentage of total composition.

EFFECT: drug delivery system ensures high bioavailability of slightly water-soluble oral drugs.

22 cl, 16 ex, 1 tbl

 

The present invention relates to an improved system for the delivery of drugs and, in particular, to an improved delivery system intended for oral administration of poorly soluble in water lipophilic drugs in dosage forms for immediate release.

It is known that the bioavailability of poorly soluble in water lipophilic drugs in oral solid dosage forms (such as tablets) is low and variable. This has led to the development of such dosage forms in which the active drug is pre-dissolved or lipid carrier, or a mixture of the latter with the surface-active substance, or in the three-component mixture of a lipid carrier + surfactant (hereinafter SAS) + co-solvent". Such a mixture provides higher bioavailability of the medicine, but only at the price of increasing the complexity of the system and, in most cases, you need to include extremely high quantities (30% or more) of the surfactant or emulsifier.

The existing delivery system for lipophilic drugs include lipophilic solutions (direct dissolution of the drug in the lipophilic carrier), self emulsifiable oil system, microemulsions, and liposomes. Features : the Tiki capabilities and applications of funds for the delivery of lipophilic drugs stated in many reviews, for example, Humberstone & Charman (1997) Advanced Drug Delivery Review, v.25, 103-128 and O Driscoll (2002) European Journal of Pharmaceutical Science, v.15, 405-415.

Lipophilic solutions

Many medicines have significant solubility in the lipophilic oils (in particular triacylglyceride). Thus, in this case, the possible form of the introduction of drugs to achieve satisfactory digestibility and bioavailability, is a simple capsule with a solution of a medicinal product. However, the expected dispersion kinetics of such systems is lower than that observed for predispersion systems. Slow dispersibility of the medicinal product is, therefore, the main drawback of this dosage form.

Self emulsifiable oil system

Self emulsifiable oil system (sometimes abbreviated as SEDDS - self-emulsifying drug delivery system, self emulsifiable system drug delivery) is a mixture of oil and surfactant, which spontaneously forms an emulsion of oil-in-water dilution with water. Solubility deliver medicines usually increases due to the presence of the surfactant to be added is usually in concentrations of 30% or more. A cosolvent, such as ethanol, propylene glycol and polyethylene glycol, are also sometimes added to the composition with the tree of increasing the solubility of the delivered drug. Dosage form in this case is a lipophilic isotropic liquid, which can be placed in capsules and being released from the capsule in the gastrointestinal tract, forms small bystrotverdeyuschie drops medicines containing oil and surfactant. The main disadvantage of SEDDS refers to the presence of large quantities of surfactants, which, in addition to the potential damaging effects on the intestinal wall, increases the complexity and cost of the dosage form. Examples of such pharmaceutical compositions are disclosed in U.S. patent No. 6436430 and 6284268.

The microemulsion preconcentrate

The microemulsion preconcentrate fundamentally similar to SEDDS and consist of isotropic mixtures of drugs, lipid, surfactant, and (if necessary) co-solvent and co-surfactant. As in the case of self emulsifiable oil systems of medicines, after getting into the aquatic environment, such systems are dispersed with the formation of dispersions of the liquid-in-liquid. The main difference microemulsion preconcentrate from SEDDS is in the nature of the formed emulsion, in which the microemulsion preconcentrate dispersed with the formation of thermodynamically stable microemulsions. It was shown that micro-emulsions improve the bioavailability of lipophil what's medicines, however, have the same major drawbacks as SEDDS, is an extremely high concentration of surfactant necessary for their education. Examples of such pharmaceutical compositions are disclosed in U.S. patent No. 5993858 and 6309665.

Liposomes

Liposomes are composed of ordered layers of phospholipid molecules that encapsulate the Central water clearance. There is a possibility of dissolution of lipophilic drugs in the phospholipid layer. Liposomal dosage forms can be used for parenteral administration, but they are not applicable in the form of dosage forms for oral administration. In addition, liposomes are unstable and expensive when you receive and, thus, have limited opportunities for transfer of lipophilic drugs. Examples of such pharmaceutical compositions are disclosed in U.S. patent No. 4746516 and 6090407.

Other dosage forms involve the conversion of microemulsions in solid or semi-solid nanoparticles and the use of polichrono. In U.S. patent No. 4999198 described polaron consisting of a continuous phase and a disperse phase containing the drug, in particular, scopolamine. The patent describes a slow release of drug from polifrone in contact with last Wednesday, in particular, transdermal drug delivery medium spans the VA. Discussed here, the invention differs from that previously described in U.S. patent No. 4999198. To date not stated about the use of such polifrone for constructing suitable for oral administration delivery systems that are compatible with hard or soft gelatin capsules. Also in the previous patent was not described specific ratios of water/lipid. Next, scopolamine is the only drug mentioned in the patent in this context.

Disadvantages of medicinal compositions for oral delivery of poorly soluble in water lipophilic drugs have been described above. None of the forms for delivery is not satisfactory.

The authors have developed legkozapominayuschihsya two-phase system for oral delivery of poorly soluble in water drugs with low water content (less than 10% by weight) and, thus, giving the system a good compatibility with gelatin, which, in turn, can be used to encapsulate drugs in hard or soft gelatin capsules. Moreover, two-phase system is easy to prepare and requires only limited amounts of potentially expensive and harmful surfactants.

In accordance with this present invention is a si is a topic for oral drug delivery, consisting of bidcactus foam containing from 1 to 20% by weight of a continuous hydrophilic phase, from 70 to 98% by weight of pharmaceutically acceptable oil, forming a continuous phase, and in the specified pharmaceutically acceptable oil is dissolved or dispersed poorly soluble in water drug in an amount of from 0.1 to 20% by weight and begincontinue foam in an amount of from 0.5 to 10%, predpochtitelno from 0.5 to 5% by weight of surfactants to form stable bidcactus foam; all ratios are given in percent by weight of the total composition.

Under used herein, the term "uidata foam, also known in this field, the term "polaron, you know anisotropic dispersion nonpolar liquid, suspended in a continuous polar phase.

Under used herein, the term "partially soluble in water drug" understand the matter, the solubility of which in water does not exceed 1% by weight. Discrete phase contains medicine in an amount of from 0.1 to 20% by weight, for example, from 1 to 10% by weight, or from 2 to 7% by weight. For some drugs it is also possible presence of a continuous hydrophilic phase, in particular, in the case of co-solvent, such as glycol.

Pharmaceutically acceptable oil, which can be used in n the standing of the invention, preferably is a mono-, di - or triglyceride or a mixture thereof. In particular, preferably used as mono-, di - or triglyceride esters of glycerol and fatty acids containing from 6 to 22 carbon atoms.

Examples of oils that can be used in the present invention, include almond oil, babassu oil, black currant seed oil, borage oil pharmacy, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cotton seeds, evening primrose oil, fish oil, seed oil grapefruit oil, mustard seeds, olive oil, palm kernels, palm oil, peanut oil, seed oil field cabbage, oil safflower dyeing, sesame oil, shark liver oil, butter, soy beans, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated oil, cotton seeds, hydrogenated palm oil, hydrogenated oil, soy beans, partially hydrogenated oil, soy, hydrogenated vegetable oil, modified triglycerides, Caprylic/capric glycerides, fractionated triglycerides, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, literitica is relat/capret, glyceryltrinitrate/capret/laurate, glyceryltrinitrate/capret/linoleate, glyceryltrinitrate/capret/stearate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, linoleic glycerides, saturated poliglecaprone glycerides, synthetic triglycerides of medium chain length, containing preferably8-C12chain fatty acids, triglycerides of medium chain length triglycerides with long chain, modified triglycerides, fractionated triglycerides, and mixtures thereof.

Examples of mono - and diglycerides used in the present invention are complex mono - and diesters of propylene glycol containing from 15 to 40 carbon atoms, including gidrolizovannogo coconut oil (for example, Campul MCM), gidrolizovannogo corn oil (for example, Maisine 35-1).

Monoglycerides and diglycerides are complex mono - and diesters of glycerol and a saturated fatty acid containing from eight to sixteen carbon atoms in the chain.

Essential oils can also be used in the present invention.

Surfactants used in the present invention, may be included in any of the phases (or both phases) bidcactus foam. Surfactants used in the present invention, is preferably a simple ether alkylpolyglycoside, ester and is of chipolopolos, ethoxylated alcohol, a complex polyoxyethylenesorbitan a fatty acid ester, complex polyoxyethylene ether fatty acids, ionic or non-ionic surfactants, adducts of hydrogenated castor oil and polyoxyethyleneglycol containing from 25 to 60 taksigrup, adducts of castor oil and polyoxyethyleneglycol containing from 25 to 45 taksigrup, ester sorbitan and fatty acids (e.g., Span 20 and Span 80), a block copolymer of ethylene oxide and propylene oxide (for example, Pluronic L121 or Pluronic F68) or mixtures thereof. Surfactants may be used in concentrations from 0.5 to 10% by weight of the total mass bidcactus foam, but preferably in concentrations of from 0.5 to 5%, most preferably from 1% to 2% by weight of the total mass bidcactus foam.

Simulator can be used to form beidseitig pins in quantities sufficient for complete dissolution of poorly soluble in water drug. Suitable simulation is phosphoglyceric, a phospholipid, such as lecithin, or free fatty acid at room temperature in the liquid state, for example, ezoterikova acid, oleic acid, linoleic acid or linolenic acid.

Continuous hydrophilic phase bidcactus foam may contain water or an aqueous phase containing an additional component for red eye reduction is of the affinity of the aqueous phase to capsulotomies material, such as gelatin. Additional material may be a salt, such as sodium chloride, or a co-solvent such as an aliphatic alcohol, a glycol, propylene glycol or glycerol, or a mixture thereof, or gelatinizing agent, such as alginate resin or their salts, guar gum, resin beans acacia, xanthan gum, gum acacia, gelatin, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and its salts, bentonites, silicates of magnesium, "Carbonari" (salt or Poperechnaya polymers of acrylic acid), or glyceryltrinitrate or their dispersion in glycol or a polymer polyvinylpyrrolidone or dispergirujutsja in water any copolymers of the above, or any suitable mixture of any of the above polymers and resins.

Otherwise, the hydrophilic phase may be non-aqueous, for example, it can represent an aliphatic alcohol, a glycol, propylene glycol or glycerol or a mixture thereof.

To increase stability bidcactus foam may be added water-soluble inorganic salts such as the salts formed by monovalent cations such as Na+, K+or NH4+, divalent cations such as Ca++or Mg++or trivalent cations such as Al+++

Poorly soluble in water drug that can be used in the present invention include the following:

analgesics and anti-inflammatory drugs:

aloxiprin, auranofin, azapropazone, benorilate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indometacin, Ketoprofen, marennikova acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac.

Deworming drugs: albendazole, bephenium hydroxynaphthoate, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, xanthelasmata, praziquantel, parentelement, thiabendazol.

Antiarrhythmic drugs: amiodarone-HCl, disopyramide, Hendershot.

Antibacterial drugs: Benjamin penicillin, cinoxacin, ciprofloxacin-HCl, clarithromycin, clofazimine, cloxacillin, doxycycline, erythromycin, ciprofloxacin, imipenem, nalidiksova acid, nitrofurantoin, rifampin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapiridin, tetracycline, trimethoprim.

Anticoagulants: dicumarol, DP is izamal, nicoumalone, phenindione.

Antidepressants: amoxapine, maprotiline-HCl, trimipramine.

Antidiabetic drugs: acetohexamide, hlorpropamid, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.

Anti-epileptic preparty: reclamed, carbamazepine, clonazepam, ethotoin, Meton, Metacritic, methylphenobarbital, phenacemide, phenobarbital, phenytoin, finaltime, primidone, Altium, valproic acid.

Antifungal drugs: amphotericin, butoconazole, clotrimazole, consolidat, fluconazole, griseofulvin, Itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole, terbinafine-HCl, terconazole, tioconazole, undecenoate acid.

Protivopodagricakih drugs: allopurinol, probenecid, sulfinpirazon.

Antihypertensive drugs: amlodipine, diazoxide, felodipine, isradipine, Minoxidil, nicardipine-HCl, nifedipine, nimodipine, prazosin-HCl, reserpine.

Antimalarial drugs: amodiaquine, chlorquin, halofantrine-HCl, mefloquin-HCl, proguanil-HCl, pyrimethamine, hemisulfate.

ANTIMIGRAINE drugs: dihydroergotamine, ArgumentError, melisagrimee, picotiterplate.

Antimuskarinovoe act occurs medicines: atropine, benzhexol-HCl biperiden, gioscia is in, mepenzolate, tropikamid.

Anticancer drugs and immunosuppressants: aminoglutetimid, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, etoposide, lomustin, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, tamoxifenside, testolactone.

Antiprotozoal drugs: kliohinol, diethylacetanilide, diloxanide, dinitolmide, furazolidone, metronidazole, nitrofurazone, tinidazole.

Antithyroid drugs: carbimazole, propylthiouracil.

Soothing, sedative, hypnotic drugs and antipsychotic drugs: alprazolam, amylobarbitone, barbiton, bromazepam, bromperidol, brotizolam, butobarbital, carbromal, chlordiazepoxid, hlormetiazola, chlorpromazine, clobazam, clozapine, diazepam, droperidol, ethinamate, fluanisone, flunitrazepam, fluororesin, flupentixol, fluphenazine, flurazepam, haloperidol, lorazepam, lormetazepam, medazepama, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbital, perphenazine, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone.

β-blockers: nadolol, pindolol.

Cardiac inotropic drugs: digitoxin, digoxin, lanatoside With, methoxy.

Corticosteroids: beclomethasone, betamethasone, budesonide, to diseasethat, desoximetasone, dexamethasone, fludrocortisone, flunisolide, fluocortolone, locationpoint, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

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

Drugs against Parkinson's disease: bromocriptine.

Gastrointestinal drugs: Bisacodyl, cimetidine, cisapride, Diphenoxylate-HCl, domperidone, famotidine, loperamide, mesalazin, omeprazole, sulfasalazin.

Antagonists H-histamine receptors: astemizole, Cinnarizine, cyclizine, cyproheptadine at-HCl, dimenhydrinate, meclozine-HCl, oxatomide, terfenadine.

Lipid regulators: bezafibrat, clofibrate, fenofibrate, gemfibrozil, probucol.

Nitrates and other drugs against angina: amylnitrate, glyceryltrinitrate, isosorbidemononitrate, pentaerythritoltetranitrate.

Vitamins: beta-carotene, vitamin a, vitamin B2, vitamin D, vitamin E, vitamin K.

Opioid analgesics: codeine, dextropropoxyphene, diamorphine, Dihydrocodeine, meptazinol, morphine, and pentazocine.

Sex hormones: klomifentsitrat, danazol, levonorgestrel, medroxyprogesterone, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, konjugierte the major estrogens, progesterone, stanozolol, stilbestrol, testosterone, tibolone.

Stimulants: dexamfetamine, dexfenfluramin, mazindol.

All of the above can be replaced by their corresponding pharmaceutically acceptable salts, isomers and derivatives. A mixture of lipophilic drugs can be used in the case of therapeutic efficacy of such combinations.

Discrete phase according to the invention contains begincontinue foam in amounts of from 70 to 98% by weight, preferably from 80 to 96% by weight, more preferably from 90 to 95% by weight. Continuous hydrophilic phase contains begincontinue foam in amounts from 1 to 20% by weight, preferably from 2 to 10% by mass.

System for oral drug delivery according to the present invention is preferably presented in unit dosage form. The preferred dosage form is a capsule filled with bidcactus foam, for example, hard or soft gelatin capsules. The use of gelatin capsules is possible due to the low water content in bidcactus foam that provides good compatibility with both hard and soft gelatin capsules, as well as due to possible inclusion in the aqueous phase is an optional component that lowers the affinity of the aqueous phase to the material to maintain the s. This is an advantage over the currently available lipid dispersions and provides potentially greater bioavailability of the medicinal product compared to tablets.

Each combined dosage form contains, for example, from 0.5 to 1000 mg, preferably from 0.5 to 200 mg medicines, for example, up to 1000 mg, preferably 100 mg per dosage form.

Begincontinue foam systems drug delivery can also be represented in the form concetrate, infinitely miscible with co-solvent such as water or compatible with water, an aliphatic alcohol, a glycol, propylene glycol or glycerol or a mixture thereof. Breeding beidseitig pen becomes possible, and they can be included in a drink, syrup or medicine cough.

Pharmaceutical compositions containing begincontinue foam according to the invention can also contain other additives, such as preservatives or antimicrobial agents (for example, to prevent microbial contamination). These additives can be included in the non-polar liquid or continuous phase.

You must understand that the inclusion of these additives is possible only at levels and with those types of materials, evidence of the effectiveness and applicability of which is known. You must be careful to choose the additive and the amount of to prevent a reduction in or complete loss of other claimed advantages of the present invention.

Methods of obtaining beidseitig pins are discussed in US-A-4486333 and suggest preliminary formation of the gas foam to obtain a sufficiently large surface for the further development bidcactus foam. It was shown that the preliminary formation of the gas foam is not a necessary condition for the formation of stable bidcactus foam, and was offered a suitable mixing mechanism in the process chamber.

Such apparatus consists of a tank equipped with a mixer, in which the blades of the agitators stirred the surface of the aqueous phase. The tank is also equipped with a delivery system for the oil phase (non-polar liquid)containing an internal phase of a disperse system. The delivery system is non-polar liquid in the reservoir is designed so that the rate of addition of liquid can be controlled and can be changed during the process. A feature of this process is that internal (oil) phase added to stir the aqueous phase slowly at first, until you have formed enough drops, forming a large surface for a more rapid formation of new droplets. At this point, the speed of adding the oil phase may be increased.

The process of forming bidcactus foam consists of the following steps:

1. Adding odgovori more surfactants to any phase or both phases (as previously defined in the experiment).

2. The premise of the aqueous phase at the bottom of the process vessel.

3. Placement in tank agitator so that it agitates the surface of the aqueous phase.

4. Bringing the stirring speed to a predetermined value.

5. Slow add internal (oil) phase, containing the poorly soluble in water, the drug is dissolved or dispersed in an oil phase, and at the same speed mixing.

6. Increase the speed of adding a predefined amount of oil phase (usually between 5 and 10% of the total added volume).

The stirring speed and the speed of adding the oil phase are variables whose values depend on the detail of design technology enterprises (in particular, the relationship of the diameter of the vessel to the diameter of the impeller), physico-chemical properties of the oil phase, and the nature and concentrations of selected surfactants. All of this can be pre-determined in a laboratory pilot study.

For specialists in this area will be clear that can also be used in other suitable technological methods.

Despite the fact that the stability beidseitig pins are usually good, however, they can be stabilized by adding a water-based gel, and, accordingly, the present izaberete the s includes a stable dispersion, containing from 1 to 80% by weight bidcactus foam and from 20 to 99% by weight of a water-based gel.

The water-based gel preferably is formed from a colloidal solution of polymer in water or aqueous suspension of the resin in amounts of from 0.05 to 20% by weight, preferably from 0.2 to 1% by weight. Suitable polymers and resins can be, for example, alginate resin or their salts, guar gum, resin beans acacia, xanthan gum, gum acacia, gelatin, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and its salts, bentonites, silicates of magnesium, "Carbonari" (salt or Poperechnaya polymers of acrylic acid), or glyceryltrinitrate or their dispersion in glycol or any suitable mixture of any of the above polymers and resins.

The present invention is further discussed with reference to the following examples:

Preparation bidcactus foam

A suitable vessel was filled with an aqueous phase bidcactus foam. The drug was dissolved in the oil phase. An oil phase containing drug was added at a constant speed using a continuous mixer or orbital mixer. After you have completed adding oil stirring was continued up until the size of the oil droplets do not become permanent or n is reached the desired value.

Example 1

The oil phase%weight (g)
Caprylic/capric triglycerides9027
Halofantrine51,5
The aqueous phase
Adduct of castor oil and polyoxyethyleneglycol (35)10,3
Deionized water41,2
Only10030,0

Example 2

The oil phase%weight (g)
Caprylic/capric triglycerides9027
Halofantrine51,5
In the of DNA phase
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (40)10,3
Deionized water41,2
Only10030,0

Example 3

The oil phase%weight (g)
Caprylic/capric triglycerides9027
Halofantrine51,5
The aqueous phase
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (60)10,3
Deionized water41,2
Only100Example 4

The oil phase%weight (g)
Oil soya bean BP9027
Halofantrine51,5
The aqueous phase
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (35)10,3
Deionized water41,2
Only10030,0

Example 5

The oil phase%weight (g)
Caprylic/capric triglycerides9027
Cyclosporine51,5
The aqueous phase
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (60)10,3
Deionized water41,2
Only10030,0

Example 6

The oil phase%weight (g)
Caprylic/capric triglycerides4012
Glycerylmonostearate (Maisine 35)4012
Cyclosporine103,0
The aqueous phase
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (60)10,3
1% aqueous solution of chloride of calcium is s 92,7
Only10030,0

Example 7

The oil phase%weight (g)
Oil soya bean BP85,525,65
Halofantrine4,51,35
The aqueous phase
Adduct of castor oil and polyoxyethyleneglycol (60)20,6
Sodium chloride10,3
Deionized water72,1
Only10030,0

Example 8

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Oil soya bean BPto 75.222,56
Halofantrine41,2
Oleic acid0,80,24
The aqueous phase
Ethanol (DEB 100)144,2
Deionized water5,61,68
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (45)0,40,12
Only10030,0

Examples 9, 10, 11, 12 are examples of dosage forms containing high concentrations of propylene glycol and a co-solvent for the poorly soluble in water, medicines.

Example 9

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Caprylic/capric triglycerides8525,5
Halofantrine41,2
Adduct of hydrogenated castor oil and polyoxyethyleneglycol (40)10,3
The aqueous phase
Propylene glycol9,52,85
Deionized water0,50,15
Only10030,0

Example 10

The following dosage form
can be prepared in the following way:
The oil phase% weight (g)
Caprylic/capric triglycerides8525,5
Halofantrine41,2
Adduct of castor oil and polyoxyethyleneglycol (35)10,3
The aqueous phase
Propylene glycol9,52,85
Deionized water0,50,15
Only10030,0

Example 11

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Oil soya bean BP8425,2
Halofantrine5 1,5
Adduct of castor oil and polyoxyethyleneglycol (35)10,3
The aqueous phase
Propylene glycol92,7
Deionized water10,3
Only10030,0

Example 12

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Oil soya bean BP8425,2
Halofantrine51,5
Adduct of castor oil and polyoxyethyleneglycol (40)10,3
The aqueous phase
Propylene glycol9,52,85
Deionized water0,50,15
Only10030,0

Example 13 illustrates the use of glycerol as a co-solvent (for poorly soluble in water, medicines) in the continuous phase.

Example 13

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Caprylic/capric triglycerides8425,2
Halofantrine51,5
C12-13 Pareth-310,3
The aqueous phase
Glycerin BP72,1
1% aqueous solution of sodium lauryl30,9
Only10030,0

Examples 14 and 15 illustrate the use of glycols as co-solvents for poorly soluble in water, medicines.

Example 14

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Caprylic/capric triglycerides8425,2
Halofantrine51,5
C12-13 Pareth-310,3
The aqueous phase
PEG-6 (polyethylene glycol)51,5
1% aqueous solution of sodium lauryl5/td> 1,5
Only10030,0

Example 15

The following dosage form
can be prepared in the following way:
The oil phase%weight (g)
Oil soya bean BP8425,2
Halofantrine51,5
Adduct of castor oil and polyoxyethyleneglycol (40)10,3
The aqueous phase
PEG-6103
Only10030,0

Example 16

To demonstrate the advantages of the present invention has been made test, which compared the dosage form according to the invention with the tablet.

Was tested commercial Lek is stunna form Galfan (Batch no. 558, SmithKline &French, UK). According to the analysis it contains 248 mg halofantrine. Bioavailability was tested on hungry males hounds and compared with that of the dosage form obtained according to example 7 (LCT BLF), except that the oil of soybeans was replaced by Caprylic/capric triglyceride (MCT BLF). Dogs (12 to 19 kg) was injected drugs in a randomized crossover trial. Dogs were fed for 21 hours before administration of a medicinal product. Blood sampling was carried out for 15 minutes before administration of the drug, and then after 15, 30, 60 and 90 minutes, and then through 2, 3, 4, 6, 8, 10, 24, 32, 48 and 72 hours after administration of the drug. The results were as follows:

The parameterTabletMCT BLFLCT BLF
Cmax(ng/ml)85176781
tmax(h)1,3the 3.82,3
AUC0-∞(ng·ml/h)113128007754
The relative bioavailability of the tablet (%)100248686

Cmax- the maximum concentration in the blood after oral administration.

tmaxthe time after oral administration necessary to achieve the Cmax.

AUC - Area under curve (area under the curve): a measure of the overall amount of drug in the blood for all time of observation after oral administration.

The relative bioavailability of the tablet (%) relative bioavailability of the dosage form is relatively tablets, expressed as a percentage.

1. Intended for oral administration system drug delivery, including begincontinue foam containing
from 1 to 20% by weight of a continuous hydrophilic phase,
from 70 to 98% by weight of pharmaceutically acceptable oil, forming a discrete phase, and in the specified pharmaceutically acceptable oil is dissolved or dispersed poorly soluble in water drug in an amount of from 0.1 to 20 mass%,
where poorly soluble drug is a drug, which dissolves in water in a quantity not exceeding 1% by weight,
and begincontinue foam comprising a surfactant in an amount of from 0.5 to 10% by weight, for shaping the Oia stable bidcactus foam, where all quantities are shown as a percentage of the total mass of unit dosage forms.

2. Intended for oral administration system drug delivery according to claim 1, where the continuous hydrophilic phase is an aqueous phase.

3. Intended for oral administration system drug delivery according to claim 2, where the aqueous phase is water.

4. Intended for oral administration system drug delivery according to claim 2, where the aqueous phase contains salt or co-solvent.

5. Intended for oral administration system drug delivery according to claim 1, where the continuous hydrophilic phase is a non-aqueous solvent.

6. Intended for oral administration system drug delivery according to claim 5, where the non-aqueous solvent is an aliphatic alcohol, polyethylene glycol, propylene glycol or glycerol, or a mixture thereof.

7. Intended for oral administration system drug delivery according to claim 1 where the pharmaceutically acceptable oil is a mono-, di - or triglyceride, or a mixture thereof.

8. Intended for oral administration system drug delivery according to claim 7, where mono-, di - or triglycerides are esters of glycerol and fatty acids containing from 6 to 22 carbon atoms.

9. Intended for oral administration delivery system Lek is rst according to claim 1, where the surfactant contains a simple ether alkylpolyglycoside, ester of alkylpolyglycoside, ethoxylated alcohol, a complex polyoxyethylenesorbitan a fatty acid ester, complex polyoxyethylene ether fatty acids, ionic or non-ionic surfactant adduct of hydrogenated castor oil/polyoxyethyleneglycol containing from 25 to 60 taksigrup, adduct of castor oil/polyoxyethyleneglycol containing from 25 to 45 taksigrup, or a mixture thereof.

10. Intended for oral administration system drug delivery according to claim 1, which includes simulator in quantities sufficient for complete dissolution of poorly soluble in water drug.

11. Intended for oral administration system drug delivery of claim 10, where simulator is phosphoglyceride or a phospholipid.

12. Intended for oral administration system drug delivery according to claim 1, where the discrete phase contains from 85 to 96% by weight bidcactus foam.

13. Intended for oral administration system drug delivery indicated in paragraph 12, where the discrete phase contains from 90 to 95% by weight bidcactus foam.

14. Intended for oral administration system drug delivery according to claim 1, where the continuous hydrophilic phase contains from 2 to 10% by weight bidcactus foam.

15. Intended for oral administration C is theme of drug delivery according to claim 1, where a surfactant is contained in amounts of from 0.5 to 5% by weight of the total composition.

16. Intended for oral administration system drug delivery according to claim 1, where poorly soluble in water, the drug is an analgesic or anti-inflammatory medicine, anthelmintic medicine, drug remedy fibrillation, anticoagulant, antidepressant, antidiabetic drug, anti-epileptic drug, antifungal drug, protivopodagricakih drug, an antihypertensive drug, antimalarial medicine, drug remedy against migraine, antimuskarinovoe act occurs drug, an antitumor drug, Antiprotozoal drug, antiheroine drug, a sedative drug, a sedative, a hypnotic agent or adjunct corticosteroid, diuretic, lekarstvennoe tool against Parkinson's disease, a gastrointestinal agent, antagonist N-histamine receptors, lipid regulator, a medicinal remedy for angina, a vitamin, an opioid analgesic, sex hormone stimulator or therapeutic mixture.

17. Intended for oral p is IEMA system drug delivery according to claim 1, representing a one-time dosage form.

18. Intended for oral administration system drug delivery by 17, where the one-time dosage form is a capsule filled with bidcactus foam.

19. Intended for oral administration system drug delivery by p, where capsules are hard or soft gelatin capsules.

20. Intended for oral administration system drug delivery according to claim 1 in the form of a dilutable concentrate.

21. Intended for oral administration system drug delivery according to claim 20, which is infinitely soluble in the co-solvent.

22. Intended for oral administration system drug delivery according to claim 1 for use in the methods of treatment of humans or animals.



 

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FIELD: medicine.

SUBSTANCE: agent for prevention and alcoholism treatment contains admixture of amidocyanogen and polylactide in the ratio (wt) from 10:90 till 40:60. The method of prevention and alcoholism treatment consists that to the patient, as a rule, enter intramusculary a solution containing an admixture amidocyanogen and polylactide in a single dose of 0.5-1.5 g once a month.

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4 cl, 3 dwg, 2 tbl, 3 ex

FIELD: medicine; ophthalmology.

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57 cl, 9 ex

FIELD: pharmaceutics.

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The invention relates to the field of molecular biology

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FIELD: medicine; biotechnologies.

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1 dwg, 8 ex

FIELD: chemistry.

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14 cl, 3 dwg, 2 tbl, 9 ex

FIELD: medicine; pharmacology.

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18 cl, 5 ex

FIELD: medicine; pharmacology.

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56 cl, 15 tbl, 15 ex

FIELD: medicine.

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45 cl, 5 dwg, 5 tbl, 2 ex

FIELD: medicine.

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44 cl, 5 dwg, 17 tbl, 9 ex

FIELD: medicine; pharmacology.

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6 cl, 4 ex

FIELD: medicine; pharmacology.

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28 cl, 16 dwg, 23 tbl, 16 ex

FIELD: medicine, veterinary medicine.

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2 ex

FIELD: medicine, veterinary medicine.

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2 ex

FIELD: medicine.

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1 tbl, 2 cl

FIELD: medicine.

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EFFECT: higher efficiency of therapy.

8 cl, 3 ex

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