BE1018506A3 - COMPOSITION OF A HYDROCORTISONE, ITS DERIVATIVES, METABOLITES, PRODRUGS OR MIXTURES, LIPOSOMAL GEL AND ITS USE. - Google Patents

Abstract

Liposomal gel containing, in addition to liposomes and a continuous phase, at least one thickener, at least one biologically active material, and, optionally, at least one excipient, characterized in that the biologically active material is encapsulated in the liposomes, and that this material consists of hydrocortisone, or its derivatives, or metabolites, or prodrugs, or any mixture thereof, and applied to the skin for therapeutic purposes.

Description

Composition of a hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing liposomal gel and its use.

The present invention relates to the composition of a hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing liposomal gel and the use thereof.

More specifically, the invention is intended for liposome gel-containing pharmaceutical compositions containing hydrocortisone, its derivatives, metabolites or prodrugs, or mixtures thereof and which are applied to the skin in an effective dose including, but not limited to, The aim is to maintain or restore hormonal balance in the body, ie for use in HRT (Hormonal Replacement Therapy), with applications in endocrinology and other specialties. Hydrocortisone in this context means the primary steroid belonging to the class of the corticosteroids, and corresponding to the chemical formula: pregn-4-en-3,20-dione, 11,17,21-trihydroxy -, (11beta) -, or 11,17,21-trihydroxy -, (11beta) -pregn-4-en-3,20-dione, or (11beta) -11,17,21-trihydroxypregn-4ene-3,20-dione, or is also known by Cortisol under the trivial names; 4-pregnene-11beta, 17alpha, 21-triol-3,20-dione; 17-hydrocorticosterone; anti-inflation hormone; Kendall's compound F; Reichstein's substance M; etc.

The molecular formula of hydrocortisone consists of 21 carbon atoms, 30 hydrogen atoms and 5 oxygen atoms, and the Chemical Abstract Service (CAS) registration number is 50-23-7.

The term metabolites of hydrocortisone in this context also includes tetrahydrocortisone, or 3,17-dihydroxy-17- (2-hydroxyacetyl) -10,13-dimethyl-2,3,4,5,6,7,8 9,12,14,15,16-dodecahydro-1H-cyclopenta (a) phenatrene-11-one, consisting of 21 carbon atoms, 32 hydrogen atoms, and 5 oxygen atoms, and better known by various synonyms.

Oral dosage forms of hydrocortisone-containing compositions are known in this connection, for example under the trade name of Hydrocortisone®, from Erfa S.A.

These and equivalent compositions and oral forms of administration tend to exhibit the following annoying disadvantages: • Very short bioavailability (only 3 to 4 hours) due to a short biological half-life of approximately 100 minutes. This implies that the intake must be repeated every 4 hours, which leads to poor compliance (compliance) and unstable serum concentrations; • The maximum plasma concentration is reached approximately one hour after taking the tablet; • High serum peaks of (supraphysiological) hydrocortisone occur approximately 1 hour after taking a tablet, which is more than 3 times higher than the physiological morning peak.

An intake four times a day then results in 4 suprafysiological serum spikes of hydrocortisone with metabolic and endocrinological consequences; • A response or increase in other stress hormones, growth hormone, thyroid hormone, testosterone and / or oestradiol may occur, due to the high serum levels, approximately one hour after taking the oral administration.

This leads in time to metabolic and hormonal disruption with the development of certain disorders; • Adrenal arrest, reversible or final, suppressing the production of adrenal cortex hormones can also occur, mainly from cortisol but also from other adrenal hormones such as testosterone, dehydroepiandrostérone and aldosterone; • Interference with biofeedback with suppression of ACTH (pituitary adrenal gonadotropin) resulting in adrenal arrest is also possible; • Fluid retention due to hypokalemia with tissue swelling and hypertension can occur.

The supraphysiological hydrocortisone serum peaks cause an increase in aldosterone - a hormone with an anti-diuretic effect.

Increases in growth hormone and estradiol can also enhance this fluid retention; • Development of Cushing Syndrome with fat distribution, diabetes, hypertension, insomnia, overvoltage, osteoporosis, skin and connective tissue weakening - as a result of suprafysiological serum peaks could sometimes be established; • Oral administration of higher doses of hydrocortisone is necessary due to the gastrointestinal loss and first pass effect due to liver passage with metabolization of the molecule in active metabolites or not; • Formation of suprafysiological concentrations of active metabolites such as tetrahydroxycortisol and tetrahydrocortisone is possible.

Also known are intramuscular or intravenously injectable compositions of bioidentical hydrocortisone, for example under the trade name of Solu-Cortef® from the company Pharmacia Corporation (Pfizer).

The annoying disadvantages of the injectable form of hydrocortisone can include the following: 1. very short bioavailability (biodisponibility); 2. no physiological diurnal varying biodisponibility possible, so no application in HRT - application in anesthesia; 3. extremely high suprafysiological serum concentrations; 4. extreme hormonal stress response, including growth hormone, testosterone, estradiol, thyroid hormone; 5. with massive metabolism of hydrocortisone in active or non-active metabolites; 6. temporary to definitive adrenal suppression.

Instead of the above-mentioned injections with hydrocortisone, it is also classical in the case of adrenal cortical insufficiency of the zona fasciculata, with insufficient production of hydrocortisone, to proceed with a replacement therapy with injectable synthetic derivatives of mineral corticoids, with or without depot effect.

In this context, known preparations include the following: 1. Methylprednisolone, under the following trade names: Methylprednisolone® (Faulding)

Solu-Medrol® (Pharmacia)

Depo-Medrol® (Pharmacia); 2. Betamethasone, with the following typical trade names:

Celstone® (Shering-Plow)

Diprophos® (Shering-Plow); 3. Dexamethasone, with the trade name:

Oradexone® (Organon); 4. Prednisolone, known by the trade names:

Deltacortril® (Pfizer)

Prednicort® (Continental Pharma)

Prednicortelone® (Continental Pharma)

Solu-Dacortine® (Merck); 5. Triamcinolone; 6. Budenonide.

The inconvenient disadvantages of the injectable form of these synthetic derivatives of mineralo-glucocorticoids replacing hydrocortisone may include the following: 1. They are not available as a bio-identical molecule; 2. They have no substitution value, they are not used as substitution in the case of adrenal cortical insufficiency, and are only applicable in emergency medicine and orthopedics; 3. They only have an anti-inflammatory effect; 4. There is no physiological diurnal release of the product.

These products release their molecule on average for 3 weeks, resulting in very high serum concentrations in the week after injection and thereafter a slow reduced availability until 3 weeks after the injection; 5. The oil suspension can only contain up to 10% of the active product; 6. The product can crystallize out intramuscularly with a decreasing depot effect as a direct consequence.

A further known disadvantage, both in the oral administration form and in the intramuscular or intravenous injectable forms, is that they are all based on substitution with suprafysiological doses of hydrocortisone, and that this increases the chance that systemic effects occur, such as: 1. Water - and electrolyte disorders: hypokalemic alkalosis, water - salt retention with sometimes arterial hypertension or even congestive heart failure; 2. Endocrine and metabolic disorders:

Cushing's Irogenrogen syndrome, reversible impaired glucose tolerance, reversible diabetes, growth stop in children, irregular menses; 3. Muscle and bone disorders:

Muscle weakness and atrophy, osteoporosis, aseptic necrosis of the hip head; 4. Gastrointestinal disorders:

Gastric and duodenal ulcers with possible bleeding and perforation;

Acute pancreatitis; 5. Skin disorders:

Acne, hypertrichosis, ecchymoses, purpura, delayed wound healing; 6. Adrenal arrest: reversible but sometimes final; 7. Eye disorders:

Cataract and glaucoma.

It is also known to use compositions containing hydrocortisone and applied to the skin as a topical or in a local form, for example as a cream, balm or ointment.

In this connection, for example, the 1% hydrocortisone ointment can be called Cremicort® from Omega Pharma or the ditto cream Cortril® from Pfizer.

These ointments or creams are, according to the official publication "Hydrocortisone Official FDA Information, side effects and uses", characterized among other things by anti-inflammatory, anti-pruritic and vaso-constituent properties, and are therefore used for that purpose, mainly in the treatment of certain skin conditions.

However, the permeability of the active ingredients through the skin is limited, for various reasons.

In this context, factors such as the integrity of the epidermal barrier play an important role, which sometimes requires the application of occlusive dressings or the application of the ointment or cream over larger skin surfaces in order to achieve the desired therapeutic effect, especially with regard to resistant forms of certain skin disorders.

The limited permeability of a typical hydrocortisone ointment or cream through the skin also means that such a cream is not at all suitable for purposes other than the topical treatment of skin conditions.

A typical composition of such an ointment or cream, for example Anusol-HC 2.5% ointment, is the following:

Hydrocortisone, active ingredient, 2.5%, processed in inactive ointment-forming components, such as benzyl alcohol, petrolatum, stearyl alcohol, propylene glycol, isopropyl myristate, polyoxyl 40 stearate, carbomer 934 (thickener), sodium lauryl sulfate, EDTA disodium salt (chelating agent), sodium hydroxide (neutralizer and pH adjustor), and water.

A typical hydrocortisone cream, for example the formula no. 0321/1326 from Actavis Mid Atlantic LLC, consists of, for example:

Hydrocortisone, active ingredient, 10 mg in 1 gram of cream, further from stearyl alcohol, glyceryl monostearate, polyoxy 40 stearate, isopropyl palmitate, parrafine, sorbitan monostearate, glycerin, lactic acid, potassium sorbate, and water.

The annoying disadvantages of the local forms may include the following: they have no system resorption, unless with long-term use of high concentrations of ointments under occlusive dressings; they only find application in dermatology; and have a high local effect, with typical local side effects due to prolonged local application such as: * irreversible atrophy with connective tissue weakness, stretch marks, bruises, hematomas, bleeding; * causing ulcers or wounds, and impaired wound healing; * they can facilitate secondary infection of the skin and / or wounds.

Finally, the local corticoids do not offer causal treatment: the condition returns after stopping treatment.

The object of the invention is to realize a composition to apply a pharmaceutically effective concentration to the skin in a dosage form containing hydrocortisone, its derivatives, metabolites, prodrugs, or mixtures thereof as active ingredient (s), and to the aforementioned and other disadvantages offers a solution, in particular to the disadvantages associated with the oral form, the topical, the injectable intramuscular (depot) preparations, or the intravenously injectable preparations.

A further objective of the invention is to provide a hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing a composition in such a galenic form that they are applied in effective concentration to healthy skin such that the permeability of the hydrocortizone is derivatives, metabolites, prodrugs or mixtures thereof, through healthy skin, allows the composition to be used without noticeable side effects, including but not exclusively, in Hormonal Replacement Therapy (HRT), in endocrinology, or in other specialties.

A further object of the invention is to offer the pharmaceutically active hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing a package which makes it possible to weigh or offer a predetermined dose thereof easily and precisely.

These objectives are achieved by formulating and using a liposomal gel which, in addition to liposomes and a continuous aqueous phase, contains at least one thickener, at least one biologically active material, and, optionally, at least one excipient, the biologically active material in the liposomes are encapsulated, and wherein this material consists of hydrocortisone, its derivatives, metabolites or prodrugs, or a mixture thereof, and is applied to the skin for therapeutic purposes.

The term "liposomes" is to be understood in a broader sense in this context and also includes liposomes of the niosome type, which are made up of nonionic amphiphiles and contain an aliphatic saturated lipophilic chain along the lipophilic side.

These objectives are also achieved by offering the gel in an easily dispersible form, for example by using a container provided with a hand-operated pump, or by packaging it, for example, in soft gelatin capsules containing a certain desired pharmaceutically effective dose and that can be easily opened for use.

A major advantage of a gel according to the invention is that the composition can be administered transdermally.

A further advantage is that the concentration of active ingredient, in particular of the fat-soluble bio-identical molecule of hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof, can be increased to above 10%.

A still further advantage is that the gel according to the invention can be used with the purpose of HRT (hormonal replacement therapy), in particular to replace certain classical galenic forms, namely the oral form, the topical or local form, the intramuscular and intravenous injectable form without exhibiting its inherent disadvantages.

A further advantage of the invention is that the gel can be applied without causing the traditional long-term system side effects or the long-term skin abnormalities at the application site.

A further advantage of the invention is that it allows to administer lower daily doses of hydrocortisone, its derivatives, metabolites or prodrugs or mixtures thereof with the achievement of normal physiological diurnal variations of serum concentrations and with excellent compliance.

Another advantage is that lower doses can be used to achieve the same therapeutic effect through administration via the transdermal form because there is no gastrointestinal loss or "first pass effect" due to passage through the liver with metabolization of the active molecule in metabolites, active or inactive.

A further major advantage of the invention is that, due to the specific transdermal disponibility of the cortisone, its derivatives, metabolites, prodrugs or mixtures thereof, the hydrocortisone liposomal gel is able to combine natural adrenal cortisone, natural diurnal production of hydrocortisone without imitating the above and other disadvantages.

A further advantage is that the gel according to the invention is applicable to a very large area, such as, but not exclusively, in the treatment of: 1. Endocrine disorders • due to primary or secondary adrenal cortex insufficiency or limited adrenal cortical reserve; • surgical procedures, serious illness or trauma in patients with adrenal insufficiency or doubtful adrenal cortex reserve; 2. Non-endocrine disorders • Allergic states • Respiratory disorders • Anesthesia / surgery • Dermatology • Rheumatology • Intensive care 3. Treatment of various disorders such as • migraine • anorexia • hypotension • pregnant sheep's neck and due to low hydrocortisone serum value (vomiting, nausea, maternity mask, fatigue, early contractions ..) • fibromyalgia, • Chronic Fatigue Syndrome, CFS.

With the insight to better demonstrate the characteristics of the invention, a few preferred compositions and applications of the liposomal hydrocortisone, derivatives, metabolites, prodrugs or mixtures thereof containing gel according to the invention are described below, by way of example and without limitation.

Classic liposomes can be considered as artificially synthesized microscopically small vesicles, usually spherical in shape, formed by one or more concentric layers, also called lamellae, consisting of lipids.

The latter are compounds which, on the one hand, have a lipophobic-hydrophilic part and, on the other hand, a lipophilic-hydrophobic part.

These slats are in principle largely or as a whole composed of phospholipids that also form the main component of the cell membrane in living beings.

Thus, for forming the liposome wall, phospholipids are used which contain mixed lipid chains and come from nature, or which are generally selected from the group of: lecithin, phosphatidyl-ethanolamine, lysolecithin, lyophosphatidyl-ethnaolamine, phosphatidylserine, phosphatidylinositol , sphingomyelin, cardiolipin, forsfatidic acid, cerebroside, stearylamine, dipalmitoyl-phosphatidylcholine, phosphatylcholine, dioleolyl-phosphatidylethanolamine, or equivalent.

Within the vesicles formed by the liposomes, an active agent can be applied, such as, for example, hydrocortisone in the case of the invention, which then applies the biologically and therapeutically active material in a controlled manner upon application of the hydrocortisone-containing liposomes to the skin. which ultimately leads to complete transdermal absorption of this material.

The hydrocortisone, its derivatives, metabolites, prodrugs or liposome-containing mixtures can be prepared according to classical preparation methods, such as described in, inter alia, Biochemica & Biophysica Acta, 475, (1976), 259-302 (authors DATyrell, TDHeath, CMColley and BERyman.)

However, the specific method of making the liposomes of the invention and enclosing the desired active ingredient or components is not critical.

In a preferred embodiment use is made of a so-called Microf loudizer® from the company

Microfluidics Corp.

The operation and use of such devices is described in detail in Biochemica &

Biophysics Acta, 775, 169-174 (1984) by Mayhew et alia, "Characterization of Liposomes Prepared using a Microemulsifier."

In a further preferred embodiment, the hydrocotrisone, its derivatives, metabolites, prodrugs or mixtures thereof containing liposomes are prepared by using ultrasonication techniques, or by forming so-called reverse phase preservers, or by hydration of thin films, or by dialysis of detergents. .

In a further preferred embodiment, the hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing liposomes according to the invention are first lyophilized before being rehydrated in a further step.

Finally, the hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing liposomes are emulsified or suspended in an adapted gel.

In a preferred embodiment, they are mixed for this purpose in a suitable mixer with gel matrices that form a polymeric three-dimensional structure around the liposomes, such as, for example, with a hydrogel consisting of neutralized carbomer, in particular Carbopol 934 ® or 941.

Both in the hydrocortisone, derivatives, metabolites, prodrugs or mixtures thereof including the enclosed phase, as well as in the external gelled continuous aqueous phase, as well as in the membrane or membrane building phase, auxiliary substances may be incorporated, selected for example from the group consisting of : sterols to increase stability and permeability, skin softeners (emollients), vitamins such as ascorbyl palmitate or vitamin D3, nutrients (nutrients), moisturizers (moisturizers), preservatives, radical absorbers, antioxidants, chelating agents such as di-EDTA salt , dyes for recognizing the concentration of active substance, mixtures of different polyethylene glycols, poloxamers such as, for example, ABA block copolymers with a wide variation of the ratio of polyetylene to polypropylene pieces, surfactants such as, for example, dodecyl sulfate, different salts, etc.

Finally, the hydrocortisone, its derivatives, metabolites, prodrugs or mixtures thereof containing liposomal gel according to the invention is conveniently placed in a dosage unit capable of offering a desired therapeutically effective amount of the gel for application to the skin, e.g. to use a manually operated pump system.

In another preferred embodiment, the gel according to the invention is presented and packaged, for example, in soft gelatin capsules which contain a desired therapeutically effective amount of the gel and can easily be broken open for use.

According to a practical preferred method, in case of application of the invention in the context of Hormonal Replacement Therapy of hydrocortisone, for example, one proceeds as follows.

The imitation of the diurnal production of hydrocortisone amounts to the achievement of morning serum spike of hydrocortisone that is max 25 μg / dl, a serum concentration of hydrocortisone that starts to decrease from about 4 hours after application to finally fall back to the basic level of the patient fall back about 15 hours after application.

The target cortisoluria for a 24-hour urine collection is then a free urinary cortisol of max 90 μg / day and 17 -OH steroids (calculated) of max 35 μΓηο1 / 24 hours.

These serum values / cortisoluria, which are the result of the patient's own adrenal production plus the result of the biodisponibility of the transdermal hydrocortisone liposomal gel applied to the skin, are brought to the desired level by using appropriate therapeutic doses of the latter. taken into account.

As special measures, the following parameters should be specially monitored, as is the case with oral and injectable forms. In the latter case, these are in particular: • The glucose level • The Arterial blood pressure • The Serum potassium content • Infectious complications

The following is also applied: • Glucose and sodium restriction • Antituberculous prophylaxis

The possible drug-drug interactions with the aforementioned oral and injectable form are not forgotten, in particular: 1. Due to hypokalemia (under EKG control) • Erythromycin • Certain anti-arrhythmics • Digitalis • Potassium-lowering agents 2. Due to alteration of the active plasma levels: • Acetylsalicylic acid • Insulin, metformin and glucose-lowering sulfamides • Phenobarbital, phenytoin, primidone, rifanpycin; 3. Due to worsening of the risk of bleeding: • Oral anticoagulants and heparin; 4. Other combinations to avoid are the following: • Anti-hypertensive agents • Alpha-interferon • Live attenuated vaccines

The present invention is by no means limited to the exemplary compositions, embodiments, and methods described and illustrated, but such methods, compositions, and embodiments can be implemented in various variants without departing from the scope of the invention.

Claims (12)

A liposomal gel containing, in addition to liposomes and a continuous phase, at least one thickener, at least one biologically active material, and, optionally, at least one excipient, characterized in that the biologically active material is encapsulated in the liposomes, and that this material from hydrocortisone , or consists of its derivatives, or metabolites, or prodrugs, or a mixture thereof, and is applied to the skin for therapeutic purposes. The gel according to claim 1, characterized in that the liposomes are emulsified or suspended in the gel. The gel according to any of the preceding claims 1-2, characterized in that the continuous phase is an aqueous phase. The gel according to any one of the preceding claims 1-3, characterized in that the thickener consists of gel matrices that form a polymeric three-dimensional structure around the liposomes, such as, for example, a hydrogel formed by neutralized carbomer, in particular Carbopol 934 ® or 941 or similar. The gel according to any of the preceding claims 1-4, characterized in that the excipients are selected from the group consisting of sterols, skin softeners (emollients), vitamins, such as for example ascorbyl palmitate or vitamin D3, nutrients (nutrients), moisturizing substances (moisturizers), preservatives, radical absorbers, antioxidants, healing agents such as di-EDTA salt, dyes for recognizing the concentration of active substance, mixtures of different polyethylene glycols, poloxamers such as, for example, ABA block Copolymers with a wide variation of the ratio of polyetylene over polypropylene pieces, surfactants, such as dodecyl sulfate, and various salts. The gel according to any one of the preceding claims 1-5, characterized in that the liposomes are produced from phospholipids that are native to or selected from the group of: lecithin, phosphatidyl-ethanolamine, lysolecithin, lyophosphatidyl-ethnaolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolipin, forsfatidic acid, cerebroside, stearylamine, dipalmitoyl-phosphatidylcholine, phosphatylcholine, dioleolyl-phosphatidylethanolamine, or equivalent. The gel according to any of the preceding claims 1-5, characterized in that the liposomes are produced from synthetic non-ionic amphiphiles with an aliphatic saturated chain to form so-called niosomes. The gel of any one of the preceding claims 1-7, characterized in that it is used in the production of a pharmaceutical preparation for use in hormonal replacement therapy, HRT. Method for carrying out HRT (hormone replacement therapy), characterized in that it comprises applying to the skin a therapeutically effective amount of the gel according to any one of claims 1-8 for the purpose of hormone balance in the body to maintain or restore. Method according to claim 9, characterized in that the therapeutically effective amount of the gel is between 0.5 and 50%, more preferably between 1 and 35%, even better between 1 and 15%. Commercial package for presenting the gel according to claim 10, characterized in that it contains one or more dosing means, for example a dosing pump, that allow to measure and make available a therapeutically effective amount of the gel for use, or that it consists of a capsule or similar container which can be broken open for use and which contains a therapeutically effective amount of the gel. Use of the gel according to claims 1-8 for the preparation of a medicament to maintain or restore the desired hormonal serum concentration by application to healthy skin.