RU2434643C2 - Transporting filler, which contains one or more di- and/or mono-(electronic transmitting agent) phosphate derivatives or their compounds - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to transporting filler for introduction of biologically active compounds, which contains one or more C₁-C₄ alcohols, water and combination of one or more diphosphate derivatives of electronic transfer agents and one or more monophosphate derivatives of electronic transfer agents. C₁-C₄ alcohols are present in amount from 0.5 to 50% by weight. Preferably C₁-C₄ alcohol represents ethanol. Transporting filler can have the shape of vesicles.

EFFECT: transporting filler in accordance with invention increases bioavailability of biologically active compounds, in particular, pharmaceutical preparations, including cosmetic ones.

33 cl, 4 dwg, 1 tbl, 8 ex

Description

This invention relates to a carrier excipient used in the administration of biologically active compounds, and to pharmaceutical compositions containing biologically active compounds and a carrier excipient. The carrier filler enhances the efficiency of transport and delivery of biologically active compounds, in particular pharmaceuticals, including cosmetics.

The background of the invention.

In this description, when a document, act or object of knowledge is mentioned or discussed, such mention or discussion cannot be considered as an assumption that this document, act or object of knowledge, or any combination of them existed at the priority date, are well-known or, as is known associated with an attempt to solve any problem associated with this description of the invention.

The main goal of drug delivery is to obtain an appropriate biological effect at the desired site of action. The choice of the composition of the drug can be critical for its effectiveness, since the bioactivity of the drug will be below optimal if it does not have the necessary physiological and chemical properties in order for the drug to stand out from the composition at the desired site of action.

Enteral delivery involves administering the drug through the gastrointestinal tract, where the drug is absorbed and delivered by the bloodstream to the target site of action. For example, medications administered orally are absorbed through the intestines.

The chemical environment of the gastrointestinal tract is also of great importance for drug delivery. The medicine should be in a stable form at different pH levels of various parts of the gastrointestinal tract. If the drug forms a non-absorbable complex or is chemically or enzymatically destroyed, this reduces absorption. In addition, in order to be absorbed, the drug must be dissolved in the fluids of the gastrointestinal tract. When the drug precipitates, it forms solid particles and is thereby eliminated from the solution. Adsorption onto luminal solid particles leads to the fact that solid particles adsorb the drug, that is, remove it from the solution. Both precipitation and adsorption reduce drug absorption. In many cases, the destruction and formation of complexes can be avoided or, at least, minimized by a chemical method or by selecting the optimal composition of the drug so that it does not limit the digestibility of the drug.

In addition, if the medicine is absorbed through the wall of the intestine or stomach, then it must pass through the liver. The liver serves to remove foreign compounds from the body. As a result, a significant part of the drug (for example, 40-50%) can be included in the metabolism and be excreted before it reaches the bloodstream. Enteral administration of the liver can be reduced if the drug is absorbed through the shell of the mouth (buccal / sublingual) or the shell of the rectum (suppositories), however, these delivery routes are not always advisable.

Attempts to increase the bioavailability of enteric biologically active compounds were reduced either to the formation of prodrugs, for example morphine sulfate, or to the use of excipients that improve absorption.

Local delivery involves the application of drugs to any membrane of the body where the drug is absorbed and distributed. For example, drugs delivered percutaneously are delivered through the skin.

The skin is the largest organ of man; Its function is to protect internal organs from external chemical, physical and pathological hazards. Normal skin is divided into three layers: epidermis, dermis and subcutaneous tissue. The outer stratum corneum of the epidermis (stratum corneum) has the properties of strength, flexibility, high electrical resistance and dryness, which delays the penetration and spread of microorganisms. The stratum corneum is also the main barrier to percutaneous absorption of drugs. There is also a layer of sebum, which is considered a barrier to all water-based pharmaceutical formulations.

When passing through the skin, the diffusing molecule of the drug has three possible routes of entry to the deeper layers of the skin: the intercellular pathway, the transcellular pathway, and the transdermal pathway. Although the lateral diffusion of electrolytes and large molecules through derivatives can be significant, the relatively small area available for transport (0.1% of the skin surface) means that this path makes a negligible contribution to the drug flow. The main pathway for the penetration of molecules, according to the generally accepted opinion, is the intercellular pathway; therefore, many methods of enhancing the assimilation of drugs are aimed at destroying a solid structure, such as a "brick with a solution," the stratum corneum. Current theories reduce the issue of drug transfer pathways to two possible mechanisms: (i) passive transcellular and (ii) intracellular epidermal transport.

Topical application of drugs to the skin is carried out in a number of ways, including ointments, pads, solutions, subcutaneous depots, poultices, patches and transdermal delivery devices.

Interest in percutaneous drug delivery is increasing, but some fundamental limitations hinder the wider use of this technology. The main limitation for the use of percutaneous delivery is the rate of transport of the drug through the skin.

Not every medicine can be administered percutaneously at a high enough speed that its blood levels are therapeutically beneficial for systemic treatment. For example, preparations with the same molecular weight and size can be absorbed through the skin at different rates. Fentanyl, for example, penetrates the skin at a speed of 2 mg / cm ² / hour, while ephedrine at a speed of 200 mg / cm ² / hour. Therefore, the percutaneous delivery system for fentanyl is not practical either economically or economically, despite the advantages of this route of administration.

Amplifiers and various formulation methods have been developed to improve the absorption of drugs through the skin. Amplifiers include compounds such as capric acid, oleic acid, azone, decylmethyl sulfoxide and hydroxycinnamates, the function of which is usually to change the structure of, in particular, the stratum corneum, dissolving the lipid membrane, which improves the penetration of drugs. For example, skin absorption of progesterone during delipidation of the stratum corneum increases by 143%. This increase rises to 843% with complete removal of the stratum corneum. However, with repeated use of such aggressive methods, obvious adverse consequences occur, including contact dermatitis, redness of the skin, itching and burning, so you have to remove the patch or apply pharmaceuticals to prevent local irritation. Redness is reported to disappear within a few hours after removal of the patch. However, concerns have been raised about the long-term risk and safety of using such transdermal delivery systems, mainly because the increase in drug permeability is achieved by damaging the extremely important protective layer of the skin.

There is a need for formulations that would further increase the bioavailability of biologically active compounds.

SUMMARY OF THE INVENTION

It has been established that the efficiency, transportation and delivery of biologically active compounds can be improved if they are introduced in an excipient containing one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives of the electronic agent transfer or their complexes.

According to a first aspect of the invention, there is provided a carrier vehicle for administering biologically active compounds, which contains one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives of an electron transfer agent or their complexes.

The invention also provides for the use of one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives of an electron transfer agent or their complexes in the manufacture of a carrier for administration of biologically active compounds.

A method for manufacturing the above transporting filler, comprising the following operations:

(a) combining one or more di- and / or monophosphate derivatives of an electron transfer agent or their complexes with one or more C _1-4 alcohols, their polyols or polymers, and

(b) adding water to the combination obtained in operation (a).

It should be understood that the transporting filler may be made from alcohol, water and phosphate derivatives of an electron transfer agent or their complexes, or be the product of their reaction. Under these conditions, alcohol, water, and phosphate derivatives of the electron transfer agent or their complexes can interact and be present in modified forms.

Preferably, the C ₁ -C ₄ alcohol is ethanol.

The carrier vehicle preferably contains one or more diphosphate derivatives of an electron transfer agent or a combination of one or more diphosphate derivatives of an electron transfer agent and one or more monophosphate derivatives of an electron transfer agent.

It should be understood that the term “one or more di- and / or monophosphate derivatives of an electron transfer agent” means phosphate esters of an electron transfer agent in which the phosphate can be orthophosphate or pyrophosphate of di- or monosubstituted electron transfer agents.

In one embodiment, the diphosphate derivative of the electron transfer agent is selected from the group consisting of ditocoferyl phosphate derivatives, ditocoferyl diphosphate derivatives, ditocotrienolphosphate derivatives, and mixtures thereof. Preferably, the diphosphate derivative of the electron transfer agent is ditocoferyl phosphate.

The monophosphate derivative of the electron transfer agent is preferably selected from the group consisting of monotocopheryl phosphate derivatives, monotocopheryl diphosphate derivatives, monotocotrienyl phosphate and mixtures thereof.

In one preferred embodiment of the invention, the composition is prepared using at least one of the following compounds: ditocoferyl phosphate, ditocoferyl diphosphate and ditocotrienol phosphate.

In another preferred embodiment, the composition is prepared using a combination of at least one of monotocopheryl phosphate, monotocopheryl diphosphate and monotocotrienyl phosphate with at least one of ditocopheryl phosphate, ditocoferyl diphosphate and ditocotrienyl phosphate.

When the composition contains a combination of monotocoferyl phosphate and ditocoferyl phosphate, these substances may be present in one or more of their alpha, beta, gamma and delta forms, preferably in alpha and gamma forms.

The ratio of monotocoferyl phosphate to ditocoferyl phosphate is preferably from 4: 1 to 1: 4, more preferably 2: 1.

Further, the present invention provides a pharmaceutical composition comprising a biologically active compound and a carrier excipient containing one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives of an electron transfer agent or their complexes .

In addition, the present invention provides a method for preparing the above composition, comprising the step of combining a biologically active compound with a carrier filler containing one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives electron transfer agent or their complexes.

Further, in accordance with the present invention, there is provided a method for administering biologically active compounds, which comprises the step of combining the biologically active compound with a carrier filler containing one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives of an electron transfer agent or complexes thereof.

The carrier vehicle may be in the form of vesicles. The biologically active compound may be at least partially encapsulated by vesicles. Not wanting to be bound by theory, we, however, believe that the formation of vesicles with controlled deformability allows the composition to cross the intercellular passages and deliver the biologically active compound intracellularly to the target cells or into the large circle of blood circulation. The di- and / or monophosphate derivatives of the electron transfer agent help counteract the inflammation caused by the administration of the composition.

DETAILED DESCRIPTION OF THE INVENTION

The carrier filler according to the invention contains one or more C ₁ -C ₄ alcohols, their polyols and polymers, water and one or more di- and / or monophosphate derivatives of the electron transfer agent or their complexes. Preferably, the amount of water present is from 50 to 99%, more preferably from 60 to 95%, most preferably from 70 to 90%.

Then, the carrier vehicle is combined with the biologically active compound, so that a drug composition is formed.

Alcohol

The term “C ₁ -C ₄ alcohol” refers to alcohols having from 1 to 4 carbon atoms, such as C _1-4 alkanols, for example methanol, ethanol, propanol, isopropanol or butanol. Polyols and polymers of C _1-4 alcohols include glycols such as propylene glycol or polyethylene glycol, for example PEG 400. Alcohol combinations can also be used. Ethanol is the preferred alcohol.

The amount of C ₁ -C ₄ alcohol present is preferably from 0.5 to 50%, more preferably from 5 to 40%, most preferably from 10 to 30%.

Phosphate derivative of electron transfer agent.

The term “electron transfer agent” in this document is an agent that can be phosphorylated and which (in non-phosphorylated form) can take an electron to form a relatively stable molecular radical or take two electrons, which allows the agent to participate in a reversible redox system. Examples of electron transfer agents that can be phosphorylated include hydroxychromanes, including alpha, beta, gamma, and delta tocols in enantiomeric and racemic forms; quinols, which are reduced forms of the electron transfer agent K1 and ubiquinone; hydroxycartinoids, including retinol, calciferol and ascorbic acid. Preferably, the electron transfer agent is selected from the group consisting of tocols, retinol, quinols, which are reduced forms of the vitamin K1 electron transfer agent, and mixtures thereof.

More preferably, the electron transfer agent is a tocol, such as tocopherol or tocotrienol. Tocols include all isomers of 6: hydroxy-2: methylchroman derivatives having the following formula (I), including α-5: 7: 8-trimethyl, β-5: 8-dimethyl, γ-7: 8-dimethyl and δ-8-methyl.

where R ₁ , R ₂ and R _{3 are} independently selected from the group consisting of hydrogen and C _1-4 alkyl, preferably methyl.

In tocopherols, R _{4 is} substituted with 4: 8: 12-trimethyltridecane, and positions 2, 4 and 8 (see *) can be occupied by stereoisomers with R or S activity or racemic. For tocotrienols, R _{4 is} substituted with a 4: 8: 12-trimethyltrideca-3: 7: 11 triene group, and position 2 may be stereoactive, for example, it may be occupied by the stereoisomers R or S, or racemic. The most preferred electron transfer agent is α-tocopherol or tocotrienol.

The term “phosphate derivative” is used herein to refer to acidic forms of phosphorylated electron transfer agents, phosphate salts, including metal salts, such as alkali or alkaline earth metals, for example, sodium, magnesium, potassium and calcium salts, as well as any other derivatives, in wherein the phosphate proton is replaced with other substituents, such as C _1-4 alkyl groups or phosphatidyl groups.

In some situations, it becomes necessary to use a phosphate derivative such as phosphatide. Phosphatidyl derivatives are aminoalkyl derivatives of organic phosphates. These derivatives can be obtained from amines having the structure R ₅ R ₆ N (CH ₂ ) _n OH, where n is an integer from 1 to 6, and R ₅ and R _{6 are} independently selected from H and C _1-4 alkyl. Phosphatidyl derivatives are prepared by replacing the hydroxyl proton of the electron transfer agent with phosphate, which then reacts with an amine such as ethanolamine or N, N'-dimethylamine. One of the methods for producing phosphatidyl derivatives uses a basic solvent, such as pyridine or triethylamine, with phosphorus oxychloride, to produce an intermediate compound that then reacts with the amine hydroxy group to form the corresponding phosphatidyl derivative, such as P-cholyl-P-tocopheryl dihydrogen phosphate.

The term “C _1-4 alcohol” refers to straight chain, branched or straight chain hydrocarbon groups having from 1 to 4 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl and cyclobutyl.

Particularly preferred phosphate derivatives of the electron transfer agent are ditocopheryl phosphate derivatives, ditocopheryl diphosphate derivatives, monotocopheryl phosphate derivatives, monotocopheryl diphosphate derivatives and monotocotrienyl phosphate derivatives; most preferred is a combination of monotocoferyl phosphate derivatives and ditocoferyl phosphate derivatives.

The stability of the carrier filler has been found to increase with increasing concentration of an electron transfer agent such as mono-α-tocopheryl phosphate. If a combination of mono-α-tocopheryl phosphate and ditocoferyl phosphate is used, their ratio is preferably from 4: 1 to 1: 4, more preferably 2: one.

The amount of phosphate derivative of the electron transfer agent present is preferably up to 11%, more preferably from 1 to 11%, most preferably from 1 to 3%.

Complex of phosphate derivative of electron transfer agent.

In some situations, if additional properties are required, such as increased stability or improved delivery, complexes of phosphate derivatives of an electron transfer agent can also be used. The complex is the reaction product of one or more phosphate derivatives of electron transfer agents with one or more complexing agents selected from the group consisting of amphoteric surfactants, cationic surfactants, amino acids with nitrogen functional groups, as well as proteins rich in such amino acids , for example, those described in international patent publication No. WO 02/40034, incorporated herein by reference.

Preferred complexing agents are selected from the group consisting of amino acids, such as arginine and lysine, and tertiary substituted amines, such as amines of formula (II)

where R ₇ is selected from the group consisting of C _6-22 alkyl, which may be interrupted by carbonyl, and

R ₈ and R _{9 are} independently selected from the group consisting of H, CH ₂ COOX, CH ₂ CHOHCH ₂ SO ₃ X, CH ₂ CHOHCH ₂ OPO ₃ X, CH ₂ CH ₂ COOX, CH ₂ COOX, CH ₂ CH ₂ CHOHCH ₂ SO ₃ X or CH ₂ CH ₂ CHOHCH ₂ OPO ₃ X, where X represents H, Na, K or alkanolamine,

provided that R ₈ and R ₉ are not both H, and when R ⁷ is RCO, then R ⁸ is NCH ₃ and R ⁹ is (CH ₂ CH ₂ ) N (C ₂ H ₄ OH) -H ₂ CHOPO ₃ , or R ⁸ and R ⁹ together form N (CH ₂ ) ₂ N (C ₂ H ₄ OH) CH ₂ COO.

Preferred complexing agents include arginine, lysine or lauryliminodipropionic acid, where complexation occurs between the main center on nitrogen and the phosphoric ester to form a stable complex.

The term “C _6-22 alkyl” refers to straight chain, branched or straight chain hydrocarbon groups having from 6 to 22 carbon atoms. Examples include hexyl, cyclohexyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl.

Biologically active compound.

The term "biologically active compound" means compounds that have a biological effect on humans or animals in medical, veterinary or cosmetic use. Biologically active compounds include drugs or their derivatives, in particular phosphate derivatives. Medicines include vitamins, phytochemicals, cosmetic agents, nutraceuticals, peptides, polypeptides, proteins or amino acids. It should be understood that some of the biologically active compounds may be included in more than one of these classes.

Examples of biologically active compounds include, but are not limited to, narcotic analgesics such as morphine, oxycodone and levorphanol; mild opioid agonists such as codeine and propoxyphene; mixed opioid agonists such as buprenorphine and pentazocine; opioid antagonists such as naloxone and naltrexone; non-opioid analgesics such as acetaminophen and phenacetin; corticosteroids such as cortisone; inhaled anesthetics such as halothane, enflurane; intravenous anesthetics, barbiturates, benzodiazepines, opioids, antipsychotics (e.g. droperidol with fentanyl), ketamine and propofol; local anesthetics such as procaine and lignocaine; antiemetics such as scopolamine; sympathomimetic agents such as adrenaline and dopamine; adrenergic agonists such as direct-acting agonists (e.g., dobutomine and epinephrine), indirect-acting agonists (e.g., amphetamine and tyramine) and direct and indirect (mixed) action agonists (e.g., ephedrine and metaraminol), adrenergic antagonists, such as alpha blockers (e.g. prazosin and phentolamine), beta blockers (e.g. atenolol, timolol and pindolol), as well as drugs that interfere with the absorption and withdrawal of neurotransmitters (e.g. cocaine, reserpine and guanethidine); anticholinergics, such as antimuscarinic agents (for example, atropine and atropine phosphate), ganglion blockers (for example, nicotine and mecamylamine), neuromuscular blockers (for example, atracurium and tubocurarine); direct-acting cholinergic agonists such as pilocarpine; cholinergic agonists of indirect action (reversible and irreversible), such as neostigmine and echothiopath; Parkinson's disease medications such as amantadine, levodopa, tolcapone, ropinirole, selegiline and bromocriptine; hormones and fragments thereof, such as sex hormones, human parathyroid hormone (PTH), growth hormone and insulin; antidiabetic agents such as insulin, glucagon-like peptides and hypoglycemic agents such as sulfonylureas, biguanides, α-glucosidase inhibitors and tiazolidinediones; anti-stenocardia drugs, such as organic nitrates (for example, isosorbide and nitroglycerin), ranolazine, b-blockers and calcium channel blockers (for example, diltiazem, nifedipine and verapamil); anti-anxiety and hypnotics, such as benzodiazepines (e.g., alprazolam and diazepam), buspirone, hydroxyzine, zolpidem, barbiturates (e.g., phenobarbital) and non-barbiturate sedatives (e.g., antihistamines and chloral hydrate); psychomotor stimulants such as amphetamine, caffeine, cocaine, theophylline and nicotine; antidepressants such as tricyclic / polycyclic antidepressants (e.g. amitriptyline), selective serotonin reuptake inhibitors (e.g. fluoxetine), monoamine oxidase inhibitors (e.g. phenelzine), antipsychotics such as typical antipsychotics (e.g. phenothiazines and phenothiazines and haloperidol) and atypical antipsychotics (e.g. benzisoxazoles, dibenzodiazepines and thienobenzodiazepines such as risperidone, clozapine and olanzapine); antiepileptic drugs such as carbamazepine, benzodiazepines, hapapentin, tiagabin, topiramate, vigabatrin, lamotrigine, ethosuximide, valproic acid, barbiturates and phenytoin; anti-congestive heart failure agents such as vasodilators, diuretics, and inotropic agents (for example, cardiac glucosides, beta-adrenergic agonists, and phosphodiesterase inhibitors); vasodilators, such as ACE inhibitors (e.g. enalapril), hydralazine, isosorbide and monoxidil; diuretics, such as thiazide diuretics (e.g., hydrochlorothiazide), loop diuretics (e.g., frusemide), potassium-sparing diuretics (e.g., amiloride), and carbonic anhydrase inhibitors (e.g., acetazolamide); cardiac glucosides, such as digoxin; β-adrenergic agonists such as dobutamine; phosphodiesterase inhibitors such as amrinone and milrinone; antiarrhythmic drugs such as sodium channel blockers (e.g. disopyramides, flecanide, liuokain), β-blockers (e.g. metoprolol, esmolol and propranolol), potassium channel blockers (e.g. amiodarone and sotalol), calcium channel blockers (e.g. diltiazem and verapamil), adenosine and digoxin; antihypertensive agents such as diuretics (e.g. thiazides, loop diuretics and potassium-sparing diuretics), beta blockers (e.g. atenolol), PTF inhibitors (e.g. enalapril and ramipril), angiotensin II antagonists (e.g. losartan), calcium channel blockers for example, amlodipine, nifedipine and verapamil), alpha blockers (for example, doxasosin, prasosin and terasosin) and others, such as clonidine, diazoxide and hydralazine; platelet inhibitors such as abciximab, aspirin, clopidrogel and tirofiban; anticoagulants such as enoxaprine, heparin and warfarin; thrombolytic agents such as alteplase, streptokinase and urokinase; bleeding agents such as aminocaproic acid, tranexamic acid and vitamin K; agents used for anemia, such as erythropoietin, iron, folic acid and cyanocobalamin; thrombin inhibitors such as lepirudin; antimicrobial agents, such as those acting against one or more anaerobic organisms, gram-positive organisms and gram-negative organisms; antimicrobial agents with a wide spectrum of action (for example, tetracycline and chloramphenical), a narrow spectrum of action (for example, isoniazid) and an extended spectrum of action (for example, ampicillin); antimicrobial agents that inhibit metabolism (e.g. sulfonamides and trimethoprim), inhibit cell wall synthesis (e.g. (β-lactams and vancomycin), inhibit protein synthesis (e.g. tetracyclines, aminoglycosides, macrolides, clindamycin and chloramphenicol) and inhibit nucleic function or synthesis acids (e.g. fluoroquinolones and rifampicin); antimicrobials used to treat tuberculosis and leprosy; antifungals such as amphotericin B, fluconazole, flucytosine, itraconozole, ketoconazole, clot imazole, econazole, griseofulvin, miconazole and nystatin; drugs used against protozoa, chloroquine, metronidazole, mefloquine, pyrimethamine, quinacrine and quinidine; anthelmintics such as praziquantel and mebendazole; antiviral agents for the treatment of respiratory infections and amidiridin infections (e.g. remantadine), for the treatment of herpes and cytomegalovirus infections (e.g., acyclovir, cidofovir, penciclovir, famciclovir, ganciclovir and vidarabine), for the treatment of human immunodeficiency virus infected (e.g. ab Kavir, adefovir, apmrenavir, delaviridin, didanosine, stavudine, zalcitabine and zidovudine) and for the treatment of hepatitis, leukemia and Kaposi's sarcoma (e.g. interferon); anticancer drugs such as antimetabolites (e.g. cytarabine, fludarabine, 5-fluorouracil, 6-mercaptopurine, methotrexate and 6-thioguanine) and antibiotics (e.g. bleomycin, doxorubicin, daunorubicin and plicamycin), alkylating agents (e.g. carmine cyclophosphamide, ifosfamide, streptozotacin and mechlorethamine), microtubule inhibitors (for example, navebin, paclitaxel, vinblastine and vincristine), steroid hormones and their antagonists (for example, aminoglutethimides, estrogens, flutamide, gosereloin, pre-lelein, ene), as well as others such as asparaginase, cisplatin, etoposide, interferons, and procarbazine; anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs (e.g., aspirin, diclofenac, ibuprofen, naproxen, sulindac, piroxicam, feilbutazone, tolmetin, indomethacin and ketoprofen), cyclooxygenase 2 inhibitors (e.g. celecoxib irofoart, iroecart, irofoart, gold salts, methotrexate and D-penicillamine) and gout treatments (e.g., allopurinol, colchicine, probenecid and sulfinpyrazone); physiologically active substances and their antagonists, such as prostaglandins (e.g. carbopost, misoprostol and dinoprost), H1 antihistamines (e.g. cliclizine, meclizine, dimenhydrinate, diphenhydramine, fexofenadine, cetirizine and loratadine), H2-antihistamidines, e.g. , nizatadine and ranitidine) and agents used to treat migraines (e.g. β-blockers, dihydroergotamine, ergotamine, metisergide and sumatriptan); asthma medications, such as beta-adrenergic agonists, corticosteroids, prophylactic anti-inflammatory drugs (e.g. cromolyn and nedocromil) and cholinergic antagonists (e.g. ipratropium); agents affecting the respiratory system, for example, aimed at the formation or function of leukotrienes (for example, montelukast, zileyton and zafirlukast); anti-allergic rhinitis agents, such as antihistamines, alpha-adrenergic agonists, corticosteroids and prophylactic anti-inflammatory drugs, such as cromoline; anti-obstructive pulmonary disease drugs such as bronchodilators (e.g. beta adrenergic agonists and cholinergic antagonists, xanthine oxidase inhibitors such as theophylline) and glucocorticoids; steroid hormones and their antagonists such as estrogens (e.g., estradiol, mestranol and hinestrol), selective estrogen modulators (e.g., raloxifene), progestins (e.g., hydroxyprogesterone, norgestrel, norethindrone and medroxyprogesterone), antiprogestins, (e.g. for example, danazol, nandrolone, stanozolol, testosterone, testosterone cypionate and fluoxymesterone), antiandrogens (e.g. cyproterone, finasteride and flutamide), corticosteroids (e.g. beclomethasone, cortisone, dexamethasone, fludrocortisone, etc. dnizolon and triamcinolone), and adrenocorticoids biosynthesis inhibitors (e.g., aminoglutethimide, ketoconazole, metyrapone, mifepristone and spironolactone); agents for treating osteoporosis, such as bisphosphonates (e.g., alendronate, pamidronate and risedronate), calcitonin, calcium and estrogens; anti-obesity agents such as lipase inhibitors (e.g., orlistad), anti-obesity peptides (e.g., growth hormone and fragments thereof) and sympathomimetic agents; treating stomach ulcers and inflammation, such as proton pump inhibitors (e.g. omeprazole and lansoprazole), antimicrobials, prostaglandins (e.g. misoprostol), and H2 antihistamines (e.g. ranitidine); antibodies; agents for thyroid disease such as thyroxine; peptide, protein and polypeptide agents, such as nucleic acids, oligonucleotides, enzymes, cytokines (e.g., tumor necrosis factor), cytokine analogues, cytokine agonists, cytokine antagonists, hormones (e.g., calcitonin and parathyroid hormone), hormone fragments (e.g., teriparatide ), hormone analogues (e.g., growth hormone agonists, growth hormone antagonists, such as octreotide, and gonadotropin-releasing hormone analogues, such as leuprolide), insulin, insulin fragments, insulin analogs (e.g. binant analogues of human insulin, lispro, glargine, aspart and detemir), glucagon-like peptide, fragments of the glucagon-like peptide, analogues of the glucagon-like peptide (eg, exenatide), immunoglobulins, antibodies, vaccines, gene therapy agents, lipoproteins, erythrifufetidine; hormonal, protein, polypeptide, nucleic acid and oligonucleotide therapeutic agents that are direct or indirect agonists, antagonists, modulators, stimulants or inhibitors of natural hormones, proteins, peptides, polypeptides, nucleic acids and oligonucleotides; small molecular or large molecular therapeutic proteins, peptides, polypeptides, nucleic acids and oligonucleotides obtained by synthesis, by recombinant methods or by chemical modification of a natural product; synthetic or natural synthesized small molecular or large molecular therapeutic proteins, peptides, polypeptides, nucleic acids and oligonucleotides; small molecule therapeutic peptides, such as growth factors, hormones, cytokines and chemokines; analogues, fragments and variants of natural proteins, peptides, polypeptides, oligonucleotides and nucleic acids and similar compounds (for example, hematide - a variant of erythropoietin and octreotide - an analog of somatostatin); hormones, proteins, peptides, polypeptides, oligonucleotides and nucleic acids for the treatment or prevention of diseases of humans and animals, such as allergies / asthma, arthritis, cancer, diabetes, growth failure, cardiovascular diseases, inflammations, immunological disorders, baldness, pain, ophthalmic diseases, epilepsy, gynecological disorders, diseases of the central nervous system, viral infections, bacterial infections, diseases of the gastrointestinal tract, obesity and hematological diseases; phytochemicals such as α-bisabolol, eugenol, silybin, soy isoflavones, phytosterols and iridoid glycosides, for example, aucubin and catalpole; sesquiterpene-lactones, such as pseudo-gua-olinolide obtained from the arnica of Chamisso; terpenes such as rosmarinic acid and rosmanol, phenol glycosides such as salicylates, for example salicin, saligenin and salicylic acid, triterpenes, such as taxasterol, α-lactucerol and taraxacoside; hydroquinone derivatives such as arbutin; phenylalkanones such as gingerols and shogaols; hypercin; antidyslipidemic agents, such as HMGCoA reductase inhibitors (e.g. simvastatin, atorvatstatin and pravastatin), fibrates (e.g. clofibrate and gemfibrozil), niacin, probucol, cholesterol absorption inhibitors (e.g. ezetimibe), antagonists of transfer, cholesterol boosters with high-density lipids (for example, torcetrapib); triglyceride lowering agents (for example, fibrates), V-protectors (for example, AGI-1067), variants of human apolipoprotein (for example, ETC-216); acylphloroglucides such as xanthohumol, lupulon, humulon and 2-methylbut-3-en-2-ol; nutraceuticals, such as wellness and other additives, vitamins, for example coenzyme Q and retinol (vitamin A), nutrients, hormone precursor molecules, proteins, for example elastin, collagen and insulin, amino acids, plant extracts, such as grape seed extract , ephedrine, dehydroepiandrosterol, isoflavones and phytosterols, as well as cosmetics such as anti-aging or anti-wrinkle products, such as elastin and collagen, and antioxidants such as retinol and coenzyme Q, retinic acid, omega-3 fat acids, glucosamine, phosphate derivatives of gamma-tocopherol and gamma-tocopheryl.

It is understood that pharmaceutically acceptable salts and derivatives of the pharmaceuticals described above are also within the scope of the present invention.

Preferably, the amount of biologically active compound is up to 5%, more preferably from 0.5 to 3%, most preferably from 0.5 to 2%.

Vesicles.

The vesicles, when present, can have a diameter of from 50 to 10,000 nm, more preferably from 100 to 500 nm, most preferably from 300 to 500 nm.

The biologically active compound may be at least partially encapsulated by vesicles.

Types of introduction.

Formulations of the invention include formulations for parenteral, enteric, oral, topical, transdermal, ophthalmic, rectal, vaginal, intranasal and intrapulmonary use. The compositions may take the form of liquids, solutions, suspensions, creams, ointments, lotions, gels, powders, aerosols, pads, enteric coated tablets, capsules, suppositories, pessaries or tampons and may be prepared by any methods known in the pharmaceutical art, for example, as described in Remington JP book Science and Practice of Pharmacy, ed. A.R. Gennaro, 20th Edition, Lippincott, Williams and Wilkins, Baltimore, Maryland (2000). These methods include combining the biological compound with an excipient and then, if necessary, forming the composition into the desired product.

The composition can be administered parenterally by injection, infusion or implantation (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms, drugs or similar delivery vehicles or implants containing conventional, non-toxic, pharmaceutically acceptable excipients and excipients.

Formulations for parenteral administration may be in unit dosage forms (for example, in ampoules with a single dose of the drug) or in vials containing multiple doses into which an appropriate preservative may be added. The composition may be in the form of a solution, suspension, emulsion, infusion agent or delivery vehicle for implantation, or it may be in the form of a dry powder that is diluted with water or another suitable diluent before use. In addition to the biologically active compound, the composition may include parenterally acceptable excipients and / or excipients. The biologically active compound can be introduced into microspheres, microcapsules, nanoparticles, liposomes and the like, providing controlled release. In addition, the composition may include suspending, dissolving, stabilizing, pH adjusting and / or dispersing agents.

As indicated above, the drug compositions may be in a form suitable for sterile injection. To prepare such a composition, the biologically active compound is dissolved or suspended in a parenterally acceptable liquid excipient. Acceptable excipients and solvents are, in particular, water, water in which the pH is adjusted to the desired value by adding an appropriate amount of hydrochloric acid, sodium hydroxide or an appropriate buffer solution, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate). In cases where one of the compounds is poorly soluble in water, a dissolution enhancing or dissolving agent may be added, or the solvent may contain 10-60 wt.% Propylene, or glycol, or the like.

Controlled release parenteral formulations may be in the form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions or emulsions. In addition, the biologically active substance can be introduced into biocompatible excipients, liposomes, nanoparticles, implants or infusion systems.

The materials used for the preparation of microspheres and / or microcapsules are, for example, biodegradable / bioerodible polymers such as polyglactin, poly (isobutylcinoacrylate), poly (2-hydroxyethyl-L-glutamine) and poly (lactic acid).

Biocompatible carrier vehicles that can be used in the preparation of controlled release parenteral formulations are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies.

The materials used in the implants may be non-biodegradable (e.g. polydimethylsiloxane) or biodegradable (e.g. poly (caprolactone), poly (lactic acid), poly (glycolic acid) or poly (orthoesters)).

Formulations suitable for oral administration may be discrete, such as capsules, cachets or tablets, each of which contains a predetermined amount of a biologically active compound; they can be in the form of a powder or granules, in the form of a solution, suspension or emulsion. The biologically active compound may also be presented in the form of a pill, porridge or paste. Tablets and capsules for oral administration may contain conventional excipients, such as binders, fillers, lubricants, disintegrants or wetting agents. The tablets may be coated according to methods known to those skilled in the art. Liquid oral preparations may, for example, be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product which is mixed with water or other suitable excipient before use. Such liquid preparations may contain conventional additives, such as suspending agents, emulsifying agents, anhydrous fillers, for example edible oils, or preservatives.

For topical transdermal use, biologically active substances can be part of ointments, creams or lotions, as well as patches. Ointments or creams, for example, may include a water or oil base with the addition of suitable thickening and / or gelling agents. Lotions may include a water or oil base and, as a rule, also contain one or more of emulsifying, stabilizing, dispersing, suspending, thickening or colorizing agents.

Dosage formulations suitable for topical administration in the oral cavity include lozenges containing the usually active ingredient in a taste base, usually sucrose and Arabian or tragacanth gum; lozenges contain the active ingredient in an inert basis, such as gelatin or sucrose, and Arabian gum, and mouthwashes contain the active ingredient in a suitable liquid filler.

Formulations suitable for rectal administration may be prepared in the form of suppositories. Suitable excipients include cocoa butter and other materials commonly used for this, and suppositories can be formed by mixing the biologically active compound with a softened or molten excipient (s), after which the preparation is cooled in molds.

Formulations suitable for vaginal administration may be prepared in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the biologically active compounds, excipients known to those skilled in the art.

For intranasal or intrapulmonary administration, the drug compositions can be prepared in the form of a solution or suspension, as well as in the form of a dry powder.

Solutions and suspensions are usually aqueous (with the exception of sterile or pyrogen-free water) with a physiologically acceptable co-solvent (for example, ethanol, propylene glycol or polyethylene glycols such as PEG 400).

Such solutions or suspensions may additionally contain other excipients, e.g. preservatives (such as benzalkonium chloride), solvents or surfactants such as polysorbates (e.g. Tween 80, Span 80, benzalkonium chloride), isotonicity buffering agents ( e.g. sodium chloride), absorption enhancers and viscosity enhancers. Suspensions may further contain suspending agents (e.g., microcrystalline cellulose, carboxymethyl cellulose).

Solutions or suspensions may be administered directly into the nasal cavity by conventional means, for example, a dropper, pipette or spray can. The compositions can be produced in single dose or multi-dose packages. In the latter case, it is desirable to provide a means of dosage. When using a dropper and pipette, the dosage is achieved by introducing a certain predetermined volume of the solution or suspension. In the case of a spray, this can be achieved using a metering spray pump.

Administration to the respiratory tract can also be achieved using an aerosol dosage form where the biologically active substance is packaged under pressure together with a nebulized substance such as chlorofluorocarbon, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas. The aerosol may also contain a surfactant, such as lecithin. The dose of the drug can be controlled using a metering valve.

The compounds can also be used in the form of a dry powder, for example, a mixture of a powdered drug compound with a suitable powder base, such as lactose, starch, starch derivatives, such as hydroxypropyl methylcellulose and polyvinylpyrrolidine (PVP). Powder filler in the nasal cavity forms a gel. The powder composition can be produced in unit doses, for example, capsules or cartridges from, for example, gelatin, or in blister packs, from which the powder can be administered using an inhaler such as Diskhaler (trademark of GlaxoSmithKline) or a metered dose aerosol inhaler.

Other fillers.

Specialists know what other excipients can be included in the medicinal composition. The choice of other excipients depends on the characteristics of the biologically active substance and the form of administration used. Examples of other excipients include solvents, thickeners or gelling agents, surfactants, buffers, softeners, sweeteners, disintegrants, flavoring agents, color additives, preservatives, perfumes, electrolytes, film-forming polymers, and the like. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methyl cellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include peppermint oil, wintergreen oil, cherry, orange or raspberry flavors. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite.

Typical excipients for the pharmaceutical composition of the invention include gelling agents such as carbomer (Carbopol), which is a carboxyvinyl polymer, preservatives such as methyl paraben, butyl paraben, ethyl paraben, propyl paraben and sodium benzoate, as well as buffers such as sodium hydroxide . These excipients may be present in amounts up to 5%.

A method of preparing a carrier excipient or drug composition.

A method of preparing a transporting filler comprises combining phosphate derivatives of an electron transfer agent or their complexes with alcohol, after which water is added. Then, the drug composition is prepared by adding a biologically active compound to the transporting excipient at any stage of the excipient preparation process.

Typically, the alcohol is heated to a temperature of 55 ° C or higher, after which the phosphate derivatives of the electron transfer agent are dissolved in alcohol. If the biologically active substance is soluble in alcohol, then it is added by combining phosphate derivatives of electron transfer agents and alcohol, then water is added to the required amount.

Other excipients, such as gelling agents, preservatives and buffers, may be added at any stage of the process, usually after adding water.

The components of the carrier and composition can be combined by any known mixing method, for example, shaking or stirring in a circle.

Detailed description of the drawings.

Examples will be described with reference to the accompanying drawings.

1 is a graph illustrating the average concentration of PTH in rat plasma;

figure 2 is a graph illustrating the distribution of radioactivity in the organs of rats after topical administration through the skin of TPM-I ¹²⁵ -insulin;

figure 3 is a graph of insulin levels in rat serum;

figure 4 is a graph of the average changes in the concentration of glucose in the blood after treatment with percutaneous insulin (Lispro).

Examples.

Now we describe the various options / aspects of the invention in the following examples, which are not restrictive.

Example 1

This example examines the transdermal absorption of human paratheroid hormone (fragment 1-34) (PTH) using the drug composition of the invention.

Materials and methods

Test formulations were prepared as follows. All percentages are by weight.

Ingredient TPM-01 / PTH TPM-02 / PTH PTH- (1-34) (American Peptide, USA) 0.1% 0.1% A mixture of acid forms of phosphorylated tocopheryls (TPM) containing TP: T ₂ P in a 2: 1 ratio. TP stands for α-tocopheryl monophosphate ester, and T ₂ P stands for ditocoferyl phosphate. one% one% Ethanol - twenty% Carbopol 0.4% 0.75% Methylparaben 0.1% 0.1% Water complements up to 100% complements up to 100%

Composition TPM-02 / PTH was a colloidal suspension that looked like milk. This indicated that vesicles formed.

Treatment

Sprague-dawley rats (males aged 10-12 weeks) were randomly divided into groups (groups 1 and 2, n = 6) and placed in separate boxes so that the neighbors did not lick the composition from their backs.

Experimental groups:

- group 1 - 100 mg of TPM-01 / PTH / 200 g body weight, twice a day for 24 hours;

- group 2 - 100 mg of the composition TPM-02 / PTH / 200 g of body weight, twice a day for 24 hours.

The rats were anesthetized, weighed and shaved with them an area of ~ 5 × 4 cm directly below the neck. Tails were taken from rats under anesthesia and plasma was taken to determine the level of PTH before treatment. Starting from the next day, for each rat, the corresponding dose of the composition was weighed out and rubbed into the rat skin with a finger in a glove. The composition was administered to groups 1 and 2 twice a day (morning and evening) for 24 hours. At the end of this period, the rats were sacrificed by asphyxia using CO ₂ and blood was taken by piercing the heart.

Plasma PTH analysis. Plasma was separated from the collected blood by centrifugation and stored until analysis at -20 ^° C. PTH levels in rat plasma were analyzed using the Human Bioactive PTH 1-34 ELISA Kit (manufactured by Immunotopics Inc., USA) according to with the manufacturer's instructions.

results

The average levels of PTH detected in plasma are shown in FIG.

The application of TPM-01 / PTH twice a day gave a significant (p <0.05 *) increase in the content of PTH in plasma after 24 hours. The average plasma PTH levels increased by 685 pg / ml compared with the baseline level in untreated rats. This increase in plasma is 4.5% of the total dose.

The application of TPM-02 / PTH twice a day gave a significant (p <0.05 *) increase in the content of PTH in plasma after 24 hours. This increase (1185 pg / ml) is 7.7% of the total dose and an increase of 70% compared with the composition of TPM-01 / PTH.

* Test results by student criterion.

Percutaneous administration of TPM-02 / PTH increased rat plasma PTH levels, suggesting that TPM is able to absorb PTH- (1-34) through the skin in 24 hours, significantly increasing plasma levels of PTH in comparison with untreated control animals. 72 hours after treatment, the plasma PTH content returned to baseline.

Published studies show that after subcutaneous injection of therapeutic amounts (25 μg / kg body weight), rat plasma PTH levels reach a maximum of ~ 40-60 minutes after injection and practically return to their previous level within 4 hours. Although the drug was used topically in this study, rats received a much larger dose (500 mcg / kg body weight). Given the high rate of PTH metabolism, it can be concluded that the high levels of PTH remaining 24 hours after the initial application account for only a small percentage of the total dose received. The effective dose for topical administration of TPM formulations will therefore be much greater than PTH levels measured after 24 hours.

findings

Although both TPM-01 and TPM-02 were effective in delivering PTH, TPM-02 / PTH delivered 70% more PTH to the circulatory system than TPM-01 / PTH. The composition according to the invention is more effective in delivering active substances through the skin to the pulmonary circulation.

Example 2

This describes a method for producing a 100 ml mixture of coenzyme Q (CoQ, or ubiquinone) and tocopheryl phosphate for subsequent use in pharmaceutical formulations of the invention. The final composition contains 0.5% CoQ10, 1% TPM, 10% ethanol, 1% carbopol, 0.1% methyl paraben, the rest up to 100% is MilliQ water.

Equipment and materials

Ethanol (brand AR)

MilliQ Water

Coenzyme Q (Kaneka company)

Tocopheryl phosphate mixture (TPM) containing tocopheryl phosphate (TP) and ditocoferyl phosphate (T2P) in a 2: 1 ratio by weight (Phosphagenics Ltd)

Powder Carbomer 934P USP (Croda Surfactants Ltd)

Methylparaben BP Powder (Bronson & Jacobs)

1 molar sodium hydroxide (NaOH)

Scales (Mettler AE 240)

Falcon Tube

100 ml plastic sample container

Water bath 70 ° C

Multi-Vortex Swirl Mixer

Methodology

1. 0.5 g of CoQ was weighed accurately into a 50 ml Falcon tube.

2. Precisely 1 g of TPM was weighed into the same 50 ml Falcon tube.

3. Weigh 10 g (not ml) of ethanol in a test tube. Clog tightly and mix.

4. Heated in a water bath with a temperature of 70 ° C, which contributes to the dissolution / melting of the components. Shook with a hand every few minutes until both CoQ and TPM dissolved. Left to warm until needed. At this concentration, CoQ precipitates from ethanol after cooling.

5. 80 ml of MilliQ water was measured in a 100 ml sample container. Tightly closed and placed in a water bath for 5 minutes to warm the water.

6. The heated CoQ / TPM / ethanol solution was poured directly into MilliQ water.

7. Immediately close and shake vigorously with your hand to mix the components. It turned out an opaque yellow composition. Stirred with a vortex mixer for 5 minutes.

8. Exactly 1 g of carbopol and 100 mg of methyl paraben were weighed into a laboratory boat. Gradually added to a solution of CoQ / TPM with vigorous vortex mixing between additions. Heated in a 70 ° C water bath for short periods of time to facilitate dissolution of the samples.

9. After adding the entire amount of carbopol and methyl paraben, they were mixed with a vortex mixer until all components were uniform, although at this stage the gel did not form.

10. Added 3 ml of 1 molar NaOH, sealed and shaken vigorously.

11. If the composition did not form a gel, the pH was checked. Carbopol forms an optimal gel at pH 7-8.

12. Operations 10 and 11 were repeated until a gel of the desired consistency was formed.

13. If necessary, add MilliQ water to obtain 100 g.

14. Stirred with a vortex mixer for another 5 minutes.

15. Wrap the container in foil to prevent CoQ photodegradation.

16. By the next day, all remaining pieces of undissolved carbopol absorbed water from the solution and formed transparent gel pockets. The container was shaken vigorously until the composition acquired a uniform consistency.

The composition was a colloidal suspension that looked like milk. This indicated that vesicles had formed.

Example 3

In this example, the transdermal uptake of coenzyme Q10 (CoQ10) is investigated using the composition of the invention.

Materials and methods

Ethanol (brand AR)

MilliQ water (own delivery)

A tocopheryl phosphate mixture (TPM) containing tocopheryl phosphate (TP) and ditocoferyl phosphate (T2P) in a 2: 1 ratio by weight (Phosphagenics Ltd).

Coenzyme Q (CoQ) (Kaneka, Japan)

Nivea Visage® Anti-wrinkle Q10 Day Care Wrinkle Cream (Beiersdorf)

Powder Carbomer 934P USP (Croda Surfactants Ltd)

Methylparaben BP Powder (Bronson & Jacobs)

1 molar sodium hydroxide (NaOH)

Scales (Mettler AE 240)

Falcon Tube

100 ml plastic sample container

Water bath 55 ° C

Multi-Vortex Swirl Mixer

Test compounds

CoQ control. The control composition of CoQ was used to evaluate how much CoQ10 is able to penetrate the skin in the absence of TPM. Content: 0.5% CoQ10 (Kaneka, Japan), 10% ethanol, 1% carbopol, 0.1% methyl paraben, the rest up to 100% is water.

0.5 g of CoQ10 was weighed into a 50 ml Falcon tube. 10 g of ethanol was added, weighed on a bench scale. Clog tightly and mix. Heated in a 55 ° C water bath to facilitate dissolution / melting of CoQ. Left to warm until needed. At this concentration, CoQ precipitates from ethanol after cooling. 80 ml of water was measured into a 100 ml sample container. The heated CoQ / TPM / ethanol solution was poured directly into water. It was immediately closed and shook vigorously with the hand to mix the components. Stirred with a vortex mixer for 5 minutes. A portion of CoQ10 dropped out of solution, forming an oily orange ring around the container. This cannot be avoided due to the insoluble nature of CoQ10. Precisely 1 g of carbopol and 100 mg of methyl paraben were weighed into a laboratory boat. It was poured into the composition and mixed with a vortex mixer until the consistency of all components was uniform, although at this stage the gel did not form.

Added 3 ml of 1 molar NaOH, sealed and shaken vigorously. If the composition did not form a gel, the pH was checked. Carbopol forms an optimal gel at pH 7-8. The addition of 3 ml of 1 molar NaOH was repeated, shaken and the pH was checked until a gel formed. If necessary, add water to get 100 g. Stirred with a vortex mixer for another 5 minutes. The container was wrapped in foil to prevent CoQ photodegradation. By the next day, all the remaining pieces of undissolved carbopol absorbed water from the solution and formed transparent gel pockets. Vigorously mixed with a vortex mixer until the composition acquired a uniform consistency.

TPM control. A TPM control formulation was used to determine the effect of TPM on endogenous CoQ10 levels. Content: 1% TPM, 10% ethanol, 1% carbopol, 0.1% methyl paraben, water - up to 100%. CoQ10 is absent in this composition.

1 g of TPM was weighed into a 50 ml Falcon tube. 10 g of ethanol was added, weighed on a bench scale. Clog tightly and mix. Heated in a 55 ° C water bath to facilitate dissolution / melting of TPM. Left to warm until needed. 80 ml of water was measured into a 100 ml sample container. The heated TPM / ethanol solution was poured directly into water. The composition immediately took the form of milk. They closed it immediately and shook it with a hand so that the components mixed. Stirred with a vortex mixer for 5 minutes. Precisely 1 g of carbopol and 100 mg of methyl paraben were weighed into a laboratory boat. It was poured into the composition and mixed with a vortex mixer until a uniform consistency, although at this stage the gel did not form.

Added 3 ml of 1 molar NaOH, sealed and shaken vigorously. If the composition did not form a gel, the pH was checked. Carbopol forms an optimal gel at pH 7-8. The addition of 3 ml of 1 molar NaOH was repeated, shaken and the pH was checked until a gel formed. If necessary, add water to get 100 g. Stirred with a vortex mixer for another 5 minutes. The container was wrapped in foil to prevent CoQ photodegradation. By the next day, all the remaining pieces of undissolved carbopol absorbed water from the solution and formed transparent gel pockets. Vigorously mixed with a vortex mixer until the composition acquired a uniform consistency.

TPM-02 / CoQ. The TPM-02 / CoQ composition according to the invention was prepared as described above in Example 2. Content: 0.5% CoQ10, 1% TPM, 10% ethanol, 1% carbopol, 0.1% methyl paraben, water up to 100% .

Nivea Visage® Anti-Wrinkle Q10 Day Care Cream (Beiersdorf, Germany): Nivea Visage® is a commercially available face cream advertised as an effective source of CoQ10 for the skin. Since the exact content of CoQ10 is not known, Nivea Visage® was compared with TPM-02 / CoQ by weight. The composition is unknown.

Experimental groups

Sprague-dawley rats (males aged 10-12 weeks) were purchased from the Monastic University Animal Services and acclimatized in our vivarium for at least 5 days before the start of the experiments. Animals were randomly divided into groups (n = 6) and placed in separate boxes so that the neighbors did not lick the composition from their backs. Food (standard, granular laboratory rat food; Barastoc, Australia) and water were provided without limitation.

Group 1 - did not receive formulations

Group 2 - 100 mg CoQ-control / 200 g body weight, twice a day for 24 hours

Group 3 - 100 mg TPM control / 200 g body weight, twice a day for 24 hours

Group 4 - 100 mg TPM-02 / CoQ / 200 g body weight two, once a day for 24 hours

Group 5 - 100 mg Nivea Visage® Cream / 200 g body weight, twice daily for 24 hours

Group 6 - 100 mg CoQ-control / 200 g body weight, twice a day for 48 hours

Group 7 - 100 mg TPM control / 200 g body weight, twice daily for 48 hours

Group 8 - 100 mg TPM-02 / CoQ / 200 g body weight, twice daily for 48 hours

Group 9 - 100 mg Nivea Visage® Cream / 200 g body weight, twice daily for 48 hours

The rats were anesthetized, weighed and shaved with them an area of ~ 5 × 4 cm directly below the neck. Starting from the next day, for each rat, the corresponding dose of the composition was weighed and rubbed into the rat skin twice a day (morning and evening) with a gloved finger. Rubbing was limited to those areas of the skin of the back, to which the rat could not get during grooming.

CoQ10 analysis in skin and plasma. At the end of the experiment, the rats were euthanized by asphyxia using carbon dioxide. Blood was collected by puncture in the heart in heparin-treated tubes and centrifuged to separate the plasma. The area with shaved skin was thoroughly washed with distilled water to remove residual unabsorbed CoQ10 from the surface and this area was excised. The extraction of CoQ from tissues and its quantification by high pressure chromatography was carried out mainly by the method described in the article by Aberg et al. (1992). Distribution and redox state of ubiquinone in rat and human tissues. Arch Biochem Biophys 295: 230-234.

Statistical analysis: Results were expressed as mean ± standard deviation. A student test was performed to determine if there are significant differences in the levels of CoQ extracted from both plasma and skin between different experimental groups.

results

Table I Average plasma and skin CoQ10 levels after administration of formulations The average CoQ ₁₀ in plasma (ng / ml) The average CoQ ₁₀ in the skin (μg / g) Structure 24 hours 48 hours 24 hours 48 hours Not introduced 27.67 ± 4.97 - 0.24 ± 0.04 - CoQ control 35.00 ± 6.45 36.33 ± 4.84 0.74 ± 0.20 1.73 ± 0.27 TPM control 33.67 ± 7.06 28.33 ± 5.79 0.32 ± 0.02 0.61 ± 0.12 TPM-02 / CoQ 59.33 ± 16.47 42.33 ± 8.80 6.13 ± 0.98 10.59 ± 4.08 Nivea Visage® 41.33 ± 4.59 29.83 ± 6.18 0.38 ± 0.05 0.62 ± 0.11

Plasma

The application of TPM-02 / CoQ twice a day to the dorsal region of rats yielded a significant (p <0.05) increase in the amount of CoQ10 in plasma (Table I). The average plasma CoQ10 levels after treatment with TPM-02 / CoQ increased by 114% (p <0.05) relative to endogenous CoQ10 levels observed in animals that did not receive the composition. CoQ and TPM controls, in contrast, were able to increase average CoQ10 levels by only 26% and 22%, respectively. None of the last two increases have reached statistical significance. It is important that TPM-02 / CoQ significantly (p <0.05) increased plasma CoQ10 levels by 70% compared to the CoQ control without TPM, which indicates the direct involvement of TPM with ethanol in transdermal CoQ10 absorption.

Nivea Visage® Cream increased plasma CoQ10 levels by 49% compared to control animals not receiving the formulations after one day of use. However, plasma CoQ10 levels after administration of Nivea Visage® were significantly lower (44%; p <0.05) than after administration of TPM-02 / CoQ.

Leather

The use of TPM-02 / CoQ significantly (p <0.05) increased endogenous levels of CoQ10 in the skin: by 2454% in the first 24 hours (table I). After 48 hours, this increase rose to 4312% of endogenous levels. In comparison, the CoQ and TPM controls increased the average levels of CoQ10 in the skin by 208% and 33%, respectively, in the first 24 hours and by 621% and 154% after 48 hours. Although the magnitude of the increase (p <0.05) after applying the TPM control is significant, it may seem of little interest. TPM-02 / CoQ showed an increase in the average CoQ10 content in the skin compared to the CoQ control of 728% and 512% after 24 and 48 hours, respectively.

The average levels of CoQ10 in the skin were significantly (p <0.05) increased (1513%) 24 hours after application of TPM-02 / CoQ compared to Nivea Visage® cream, which failed to increase the CoQ10 content in the skin compared to the control compounds.

findings

The TPM / ethanol formulation increased solubility and subsequent absorption of CoQ10 through the skin, significantly increasing plasma and skin CoQ10 levels compared to control formulations that included a commercially available cosmetic source of CoQ10. The preparation of preparations using the compounds together with the TPM / ethanol composition in accordance with the invention has enormous potential for topical application and assimilation of molecules characterized by poor oral bioavailability, skin specificity, or adverse digestion effects.

Example 4

A preparation containing insulin was prepared as described above. The drug had the following composition:

Ingredient TPM-02 / insulin Insulin 60 units / g of gel A mixture of phosphorylated tocopheryls (TPM) containing TP: T ₂ P in a 2: 1 ratio. TP means α-tocopheryl monophosphate ester, and T ₂ P means ditocoferyl phosphate 2% Ethanol thirty% Carbomer 934 one% Water The rest is up to 100%

Example 5

This example uses the transdermal delivery of insulin in a formulation that includes TPM.

COMPONENTS OF COMPOSITION LISPRO, a human insulin analogue (Eli Lilly). Bovine insulin (Sigma) 3- [ ¹²⁵ I] iodothyrosyl A14) insulin, human recombinant (Amersham Biosciences, code IM166, lot B0602) ( ¹²⁵ I-insulin). TPM - a mixture of α-tocopheryl phosphate (TP) and ditocoferyl phosphate (T2P; 2: 1) DOSAGE OF COMPONENTS 32.5 units LISPRO per 1 kg of body weight, 10 units. bovine insulin per 1 kg of body weight, ¹²⁵ I-insulin (human recombinant; 400 nCi) per rat, 2% TPM Experiments 1-3 Sprague Dawley Rats DESCRIPTION OF ANIMAL MODELS Gender: Male Experiment 4 Body weight range: 220-450 g Age: 10-12 ANIMAL MODELS Pigs

Four separate experiments were conducted to independently demonstrate transdermal insulin delivery using TPM formulations after topical administration. TPMs were combined with bovine insulin, a fast-acting insulin analogue (LISPRO), or a human insulin recombinant labeled with a radioactive isotope. Delivery success was evaluated by increasing plasma insulin levels, detecting subcutaneous radioactivity, or decreased blood glucose levels after glucose loading.

Experiment 1. Increased plasma insulin levels.

The skin on the back of male Sprague Dawley rats (220-300 g) was shaved under mild anesthesia (ether) the day before the experiment. While the rats were sleeping, they were weighed to calculate the dose of Nembutal and the drug composition required for each rat. Rats were left to starve overnight (~ 16 hours) with free access to water.

The next morning, the rats were anesthetized and kept under anesthesia for the entire experiment. The experimental composition contained 2% TPM, bovine insulin (3 units / 100 μl; Sigma), ethanol (30%) and carbomer (1%), the rest was water. Rats received a final insulin dose of 10 units / kg body weight. The control group received the same composition containing TPM, but without insulin. The control composition (n = 2) and the TPM-insulin composition (n = 2) were applied topically and rubbed into the skin with a gloved finger. Serum was collected at 1, 2, 3, 4, and 6 hours after administration.

To measure the amount of insulin present in serum samples, a radioactive immunoassay (Linco Research Inc.) specific for bovine insulin was used.

Experiment 2. Detection of transdermal absorption of insulin using radioactive probes.

Sprague Dawley rats (300-450 g) were prepared for topical administration of the formulations as in Experiment 1. The rats were left to starve overnight (~ 16 hours) with free access to water.

Human recombinant radiolabeling insulin ( ¹²⁵ I-insulin, Amersham Biosciences) was combined with 2% TPM, 30% ethanol, 1% carbomer and water to form a gel (TPM- ¹²⁵ I-insulin). TPM- ¹²⁵ I-insulin was applied topically (as indicated above) at a dose of ~ 400 nCi per rat (n = 4). Control rats (n = 5) received a TPM-free formulation to determine the role of TPM in transdermal delivery. After application of the drug, the rats were kept separately, with free access to food and water. After 5 hours, the rats were sacrificed, their organs were removed, weighed and placed in scintillation vials to calculate the total amount of radioactivity in each organ. The skin was washed to wash off all unabsorbed I ¹²⁵ -insulin remaining on the surface of the skin.

Experiment 3. Reducing blood glucose with transdermal insulin.

Sprague Dawley rats (220-300 g) were prepared for topical administration of the compounds as in Experiment 1. The rats were left to starve overnight (~ 16 hours) with free access to water.

The fast acting insulin analog LISPRO (Eli Lilly) was combined with 2% TPM, 30% ethanol, 1% carbomer and water to form a gel (TPM-LISPRO). The treatment group (n = 15) received topical administration of TPM-LISPRO (dose of 32.5 units of LISPRO / kg body weight) 30 minutes before glucose loading to give LISPRO time to enter the pulmonary circulation. The control group (n = 15) received the composition without LISPRO. Glucose (30% w / v) was administered intraperitoneally at a dose of 2 g / kg body weight (2 ml per rat weighing 300 g).

Rats were kept under anesthesia (Nembutal) throughout the experiment; blood was taken from the tail and glucose was measured using a Medisense Optium Blood Glucose Monitor (Abbott) blood glucose monitor. Blood glucose was measured 5 minutes after glucose administration and another 5 minutes. Then, blood glucose was measured every 10 minutes for ~ 2-2.5 hours. Blood glucose levels, measured immediately after glucose administration, were calculated from all subsequent measurement results to determine changes in this level for each rat during the experiment. For each time point, the average change in blood glucose level was calculated and plotted on a graph (FIG. 3). Since non-diabetic rats were used in this study, the effectiveness of TPM-LISPRO was judged by the reduction in peak glucose compared to control animals.

Next, the area under the curves for individual animals was calculated and population groups were compared using analysis by Student's criterion.

Experiment 4. Lowering blood glucose with transdermal insulin.

Eight pigs with two surgically inserted catheters were trained at least 5 days before the start of the study. Pigs were trained to feed at about 3:00 in the afternoon, so they were used to fasting at night. The experimental design was as follows: two doses of TPM-02 gel with insulin or TPM-02 gel without insulin. Intravenous infusions were performed with an interval of at least 1 day. On the day of the infusion, pigs were bled every 15 minutes for 1 hour to determine baseline blood glucose concentrations before application of the gels. After 30 minutes, an infusion of glucose (0.33 g / kg per hour) and xylazine (0.033 mg / kg per hour) began, and blood sampling continued for another 3 hours. Blood was immediately tested for glucose using a Glucometer. During the experiments, the catheters in one pig lost their working capacity, so only 7 pigs were included in the study. In addition, on one of the days of blood collection (insulin injection), the intake catheter in one of the pigs failed during the infusion. Therefore, the number of days of blood sampling from control and insulin-treated pigs was 7 and 6, respectively.

Blood glucose data were analyzed using the REML model with constant values, including administration of the composition (control or insulin) and time of blood sampling, while the random model included pig identification and blood sampling day. In addition, the glucose content in the blood was averaged over the period before the introduction of the compounds and the last 2 and 4 samples. These data were also analyzed using REML, with constant blood sampling times (either before or after application of the gel and infusion), while the random model included pig identification and blood sampling day. For these latter analyzes, the data was subjected to a logarithmic transformation.

Results and discussion

Preliminary Experiment 1. Increased plasma insulin levels.

In a pilot experiment, topical administration of TPM-insulin was able to increase serum insulin levels (Figure 3). In both experimental animals, increased serum insulin levels peaked 4 hours after administration. Insulin levels in control animals decreased during this period or could not reach levels such as in animals that received percutaneous insulin. The small number of animals used in this preliminary experiment means that statistical estimation is not possible; however, the positive trend for successful transdermal absorption is obvious, so further research is needed in more extensive experiments.

Experiment 2. Detection of transdermal absorption of insulin using radioactive probes.

Having received positive evidence of increased serum insulin levels in a pilot experiment, we decided to convincingly demonstrate transdermal absorption of insulin mixed with TPM. To do this, we combined TPM with a radiolabeled form of insulin to use its radioactive decay to control percutaneous absorption of radioactive insulin and its subsequent distribution (if it occurs) throughout the rat. The results show that TPM is able to successfully enhance the transdermal uptake of ¹²⁵ I -insulin (FIG. 2). The levels of radioactivity inside the skin at the site of application of the composition increased significantly (p <0.001) compared with control animals. Since the skin surface of each rat was washed, radioactivity is present in the deeper layers of the skin. It is important that subcutaneous fat immediately below the application area had significantly (p <0.05) increased levels of radioactivity compared to control animals, which convincingly demonstrates the ability of TPM to enhance the absorption of insulin through the skin into the underlying tissue.

Example 3. Reducing blood glucose by transdermal administration of insulin.

After demonstrating the successful transdermal absorption of insulin in combination with TPM, we decided to investigate whether the molecule delivered through the skin can effectively enter the pulmonary circulation to lower blood glucose. The fasting rats were tested for glucose tolerance 30 minutes after topical application of TPM-LISPRO and then the blood glucose was measured at sequential intervals (FIG. 4). Blood glucose levels decreased significantly (p <0.02) in animals treated with TPM-LISPRO compared to controls, which demonstrates both percutaneous delivery and subsequent activity of the delivered LISPRO. Consequently, TPM is capable of transporting large, active molecules such as insulin through the skin.

Experiment 4. Reducing blood glucose by transdermal insulin.

This study was a continuation of a rat study in which glucose tolerance tests showed that a transdermally administered insulin formulation penetrates the skin and becomes bioavailable. This phenomenon has now been evaluated in pigs using an intravenous glucose test with transdermal administration of TPM-02 / insulin.

The technique was improved: the oral administration of glucose, which did not work as expected, was replaced by an intravenous glucose infusion. In addition, xylazine (a chemical that inhibits the release of insulin in the pancreas) was injected with glucose.

The overall statistical effect of TPM-02 / insulin was very significant (p <0.005). Most obviously, this effect manifested itself in the last part of the infusion, when the blood glucose level reached a plateau. On this plateau, the increase in blood glucose was significantly lower in pigs receiving a transdermal insulin preparation, which represents a notable improvement in glycemic control. Data show that insulin was absorbed during transdermal administration.

The simultaneous injection of glucose and an insulin secretion inhibitor such as xylazine seems to be a good model system for measuring transdermal insulin delivery. In further work, it is necessary to expand the use of this model in order to study the effect of percutaneous delivery with a sharper increase in blood glucose levels, as well as to extend the study time to determine how long the delivery will last. Further studies can also be carried out on a model system that is more appropriate for the target organism (i.e., the body of a person suffering from diabetes), for example, a streptozotocin diabetic pig, that is, a pig that received chemical streptozotocin, which destroys pancreatic cells secreting insulin and causes pigs diabetes.

Findings.

The presented results show that a mixture of tocopheryl phosphates (TPM) can successfully enhance the transdermal uptake of large molecules such as insulin. Elevated levels of insulin were found inside the skin at the site of application, in subcutaneous fat and in the blood. It is important that glucose tests show that the molecules delivered in this way are active and able to effectively lower blood glucose levels. This is a very positive result for diabetics, as it gives them hope for the emergence of a non-invasive method of insulin delivery, which will avoid the inconvenience of daily injections.

It is proposed to conduct experiments using vertical diffusion cells (Franz cells) on the skin of pigs and humans to determine the speed of movement and permeability of various variants of the drug composition. This method will allow you to quickly optimize the composition of TPM-insulin.

Example 6

A composition containing atropine was prepared as described above. The content of the components was as follows:

Ingredient TPM-02 / atropine Atropine phosphate one% A mixture of phosphorylated tocopheryls (TPM) containing TP: T ₂ P in a 2: 1 ratio. TP stands for α-tocopheryl monophosphate ester, and T ₂ P stands for ditocoferyl phosphate 2% Ethanol thirty% Carbomer 934 one% Water The rest is up to 100%

Example 7

TPM vesicles containing a mixture of α-tocopheryl monophosphate ester (TP) and ditocoferyl phosphate (T ₂ P) in a 2: 1 ratio were exposed to artificial gastric and intestinal juices to determine if the enteral formulations of this invention are able to withstand digestive canal conditions.

The vesicles contained 2% TPM, as well as the fluorescent dye Rhodamine 6G, and analysis of the distribution of the population of vesicles was performed using fluorescent cell sorting.

Artificial gastric and intestinal juices were prepared in accordance with the United States Pharmacopeia. Gastric juice was an acidic solution of the enzyme pepsin with a pH of 1.2. Intestinal juice was prepared from pancreatin powder in phosphate buffer and had a pH of 6.8.

The vesicles were exposed to both juices separately. When exposed to artificial gastric juice, larger vesicles and / or accumulations of vesicles were created. Exposure to artificial intestinal juice had almost no effect on the appearance of the vesicles, and they retained their original size.

Example 8

A formulation was prepared containing TPM complexes corresponding to the above description. It contained the following components:

Ingredient % by weight The combination of lauryl iminodipropionic acid and a tocopheryl phosphate mixture (TPM) containing TP: T ₂ P in a 2: 1 ratio. TP is α-tocopheryl monophosphate ester, and T ₂ P is ditocoferyl phosphate. 3.2% Ethanol thirty% Water The rest is up to 100%

Vesicles were formed from this compound.

The words “comprising” or “including” and their forms used in this description and the claims do not limit the claimed invention and do not exclude any variations or additions.

Modifications and improvements to the invention will be apparent to those skilled in the art. Such modifications and improvements will be included in the scope of the invention.

Claims (33)

1. A carrier vehicle for administering biologically active compounds containing one or more C ₁ -C ₄ alcohols, water and a combination of one or more diphosphate derivatives of electron transfer agents and one or more monophosphate derivatives of electron transfer agents, wherein C ₁ -C ₄ alcohols present in an amount of from 0.5 to 50% by weight. 2. Transporting filler according to claim 1, containing polyols or polymers of C ₁ -C ₄ alcohols. 3. The transporting filler according to claim 2, in which C ₁ -C ₄ alcohols, their polyols and polymers are present in an amount of from 0.5 to 50%, from 5 to 40%, or from 10 to 30% by weight. 4. The transporting filler according to claim 2, in which C ₁ -C ₄ alcohols, their polyols and polymers are present in an amount of from 0.5 to 5%, or from 0.5 to 10%, or up to 1% by weight 5. The transporting filler according to claim 1 or 2, wherein the C ₁ -C ₄ alcohols, their polyols and polymers are selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and glycols, or combinations thereof. 6. The carrier vehicle of claim 5, wherein the C _1-4 alcohol is ethanol. 7. The transport filler according to claim 1, wherein the di- and / or monophosphate derivative of the electron transfer agent is a phosphate ester of an electron transfer agent, in which the phosphate can be orthophosphate or pyrophosphate of di- or monosubstituted electron transfer agents. 8. The carrier vehicle of claim 1, wherein the di- and / or monophosphate derivative of the electron transfer agent is selected from the group consisting of phosphate derivatives of hydroxychromanes, phosphate derivatives of quinols, which are reduced forms of the electron transfer agent of vitamin K1 and ubiquinone; phosphate derivatives of hydroxycaratinoids, phosphate derivatives of calciferol and phosphate derivatives of ascorbic acid. 9. The transport vehicle of claim 8, wherein the phosphate derivatives of hydroxychromanes are selected from the group consisting of phosphate derivatives of alpha, beta, gamma and delta tocols in enantiomeric and racemic forms. 10. The transporting filler according to claim 9, in which the phosphate derivative of tokens is a phosphate derivative of tocopheryl or a phosphate derivative of tocotrienol. 11. The transporting filler of claim 10, in which the phosphate derivatives of tocols are selected from the group consisting of ditocopheryl phosphate derivatives, ditocoferyl diphosphate derivatives, monotocoferyl phosphate derivatives, monotocoferyl diphosphate derivatives and monotocoferyl diphosphate derivatives. 12. The transporting filler according to claim 11, in which the phosphate derivative of the tocol is a ditocoferyl phosphate derivative. 13. The transporting filler according to claim 11, in which the phosphate derivative of tocol is a combination of a ditocoferyl phosphate derivative and a monotocoferyl phosphate derivative. 14. The transporting filler according to item 13, in which the weight ratio of monotocoferyl phosphate to ditocoferyl phosphate is from 4: 1 to 1: 4 or 2: 1. 15. The transporting filler according to claim 1, wherein the phosphate derivative of the electron transfer agent is present in an amount of up to 11%, 1 to 11%, or 1 to 3% by weight. 16. The transporting filler according to claim 1, in which water is present in an amount of from 50 to 99%, from 60 to 95%, or from 70 to 90% by weight. 17. The carrier vehicle of claim 1, which is in the form of vesicles. 18. Transporting filler according to 17, in which the diameter of the vesicles is from 50 to 10,000 nm, from 100 to 500 nm, or from 300 to 500 nm. 19. The carrier vehicle of claim 18, wherein the vesicles partially or fully encapsulate the biologically active compound. 20. The use of one or more C ₁ -C ₄ alcohols in an amount of from 0.5 to 50% by weight of water and a combination of one or more diphosphate derivatives of electron transfer agents and one or more monophosphate derivatives of electron transfer agents in the manufacture of a carrier for administration biologically active compounds. 21. The method of preparation of the transporting filler according to claim 1, containing the following operations:
a) combining a combination of one or more diphosphate derivatives of electron transfer agents and one or more monophosphate derivatives of electron transfer agents with one or more C ₁ -C ₄ alcohols and
b) adding water to the combination obtained in operation (a). 22. A composition containing a biologically active compound and a carrier excipient according to any one of claims 1 to 19. 23. The composition according to item 22, in which the biologically active compound is present in an amount up to 5%, from 0.5 to 3%, or from 0.5 to 2% by weight. 24. The composition according to item 22, in which the biologically active compound is a pharmaceutical agent or its phosphate derivative. 25. The composition according to paragraph 24, in which the pharmaceutical agent is selected from the group consisting of vitamins, phytochemicals, cosmetic agents, nutraceuticals, hormones, peptides, polypeptides, proteins and nucleic acids. 26. The composition according A.25, in which the pharmaceutical agent is selected from the group consisting of antipsychotic, narcotic analgesic, anti-inflammatory agent, anti-cancer agent, antihistamine, anti-stenocardia agent, anti-dyslipidemic agent, anti-diabetic agent and hormone analogue. 27. The composition according to p, in which the pharmaceutical agent is selected from the group consisting of coenzyme Q, human parathyroid hormone, insulin, glucagon-like peptide, morphine, oxycodone, elastin, retinol and collagen. 28. The composition according to item 22, optionally containing other fillers. 29. The composition according to p. 28, in which the other fillers are selected from the group consisting of solvents, thickeners or gelling agents, surfactants, buffers, softeners, sweeteners, disintegrants, flavors, color additives, preservatives, fragrances, electrolytes and film-forming polymers. 30. The composition according to p, in which other fillers are present in an amount up to 5% by weight. 31. The method of preparing the composition according to item 22, containing the operation of combining a biologically active compound with a carrier filler according to any one of claims 1 to 19. 32. A method for administering biologically active compounds, comprising the step of combining the biologically active compound with a carrier vehicle according to any one of claims 1-19, and its use by parenteral, enteral, oral, local, transdermal, ophthalmic, rectal, vaginal, intranasal or intrapulmonary administration. 33. The method according to p, in which the biologically active compound and the excipient are introduced transdermally.

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