ES2356563T3 - MEPTAZINOL TRANSDERMAL ADMINISTRATION. - Google Patents

Abstract

Transdermal device for transdermal administration of an effective amount of meptazinol to provide analgesic relief to a mammal or patient in need thereof, comprising: (i) a support layer; (ii) a layer or container compartment; (iii) a control membrane or an uncontrolled microporous membrane; (iv) an adhesive film that is optionally applied as a perimetric ring or as a geometric model or combination of both; (v) a separable coating; and so that the container layer or compartment contains a compound comprising (a) a form of meptazinol salt in an amount that results in the administration of an effective amount of meptazinol when added to the device and said device is applied to the skin; and (b) a pharmaceutically effective carrier.

Description

FIELD OF THE INVENTION

The present invention relates to the administration of a meptazinol salt for analgesic purposes and more particularly it relates to a method and device for the administration of a meptazinol salt to a patient in need thereof, over a period of time. prolonged, with an essentially constant dosage, while avoiding the first metabolic step.

BACKGROUND OF THE INVENTION

Inadequate pain relief continues to be a major problem, both for patients and for health professionals. Optimum pharmacological management of pain requires the selection of the appropriate analgesic medication 10 that achieves rapid efficacy with minimal side effects.

Gentle painkillers and over-the-counter (OTC) analgesics, such as paracetamol, are readily available for mild pain. Stronger painkillers and those that frequently require regular medication (3-4 times a day, at a minimum) have significant side effects, for example, gastric hemorrhages and / or ulceration with NSAIDs; Constipation is a significant side effect of the 15 mild opioids, for example, codeine and dihydrocodeine, while the strongest opioid analgesics, for example, tramadol, affect cognition and conscious status, in addition to presenting gastrointestinal effects secondary.

The usual therapy for the management of moderate or severe pain is suboptimal. The strongest analgesics, for example, pethidine, fentanyl, morphine and diamorphine, although they are suitable analgesics, also have significant, well-known side effects that frequently limit their use, for example, tolerance over time, gastrointestinal side effects and respiratory depression In addition, the use of the most potent analgesics is strictly controlled because of their addictive properties.

Meptazinol is a mixed agonist-antagonist analgesic with specificity for the mu1 opioid receptor that shows both opioid and cholinergic properties and its chemical structure is defined by the following formula (I): 25

The preparation of the meptazinol hydrobromide salt was indicated in US Patent 3,729,465 and the preparation of the meptazinol free base was indicated in US Patent 4,197,241.

The cholinergic properties of meptazinol are believed to contribute to its anti-nociceptive effects and to minimize the usual range of opioid side effects. Meptazinol has been shown to have a negligible probability of clinical dependence, both from the point of view of clinical research and the lack of reports of current use / abuse cases. The lack of addictive potential of meptazinol was first indicated in 1987 by internationally recognized researcher Dr. Don Jasinski (Lexington, Kentucky). This characteristic distinguishes meptazinol from many other strong analgesics, such as fentanyl (for example, Duragesic), pentazocine, oxycodone (for example, Oxycontin, Percocet) and morphine, which are classified as “controlled drugs” with restrictions consequent of prescription / dispensation.

Meptazinol also has many clinical advantages over more conventional opioid analgesics that include causing minimal respiratory depression, causing minimal sedation and lack of constipation.

Causing minimal respiratory depression makes meptazinol a preferred pain reliever in obstetrics to avoid respiratory disturbances in the child. Other analgesics administered during childbirth, such as pethidine and 40

Diacetylmorphine can cause significant respiratory depression of the child resulting in the so-called gray child syndrome, which often requires the use of a narcotic antagonist, such as naloxone to reverse this effect.

Causing minimal sedation is advantageous in the treatment of chronic pain states and helping the patient to lead a normal daily life. Sedation associated with other analgesics frequently induces lethargy and a reduction in the quality of life, with patients entering an almost twilight world.

The lack of constipation effect is an important characteristic in the treatment of chronic pain. Constipation usually associated with other strong pain relievers can be an especially annoying condition, especially for older patients. For this group of patients that is often the target population for strong analgesics, the lack of constipation effect of meptazinol represents an important advantage over 10 other strong analgesics, such as pethidine.

In addition, age is unlikely to affect the elimination of meptazinol that is performed by a simple single-stage glucuronidation process, the resulting inactive, water-soluble conjugate leaking into the kidney. This process of conjugated metabolic elimination is not affected by age like other elimination mechanisms, such as direct filtering of the active entity in the kidney or oxidative metabolic elimination, such as is required, for example, by pethidine.

However, despite these clinical advantages, the use of meptazinol has been restricted by two important disadvantages: (1) low oral bioavailability; with indicated average values that are between 4-9% as a result of an extensive first pass of metabolism and (2) a propensity, common to other strong analgesics, in causing nausea and emesis. Nausea and emesis worsen the bioavailability due to physical loss of the medication due to vomiting. In addition, since it is known that meptazinol inhibits gastric emptying and effectively traps a portion of the medication dosed orally in the stomach, larger amounts of meptazinol can be lost by emesis.

All these factors lead to highly variable plasma drug levels of meptazinol after oral dosing and as a consequence to a variable patient response. The demand for immediate relief of moderate to severe pain may be such that the patient does not wish to continue treatment with meptazinol until an optimal dose for personal use is discovered. This frustration in obtaining optimal dosage levels for each individual patient can lead to problems of adaptation and ineffective pain relief medication. The issue of adaptation is further increased by the need for frequent oral administration of meptazinol typically 4-6 times a day as a result of its short plasma half-life (1.5-2.0 hours). 30

Examples of pharmaceutical compounds comprising meptazinol hydrochloride in combination with ibuprofen in the form of tablets have been disclosed in GB 2 122 895.

The transdermal administration of strong analgesics in recent years has proven a useful alternative to injectable administration as a means of overcoming many of the problems associated with oral administration. Modulation of rapid elevation in plasma drug levels, which is usually seen after oral administration, can serve to minimize emesis associated with comparatively high Cmax values resulting from rapid absorption. In the specific case of meptazinol, avoiding emesis is more important to minimize the loss of the drug trapped in the stomach due to its inhibitory effects on gastric emptying.

Transdermal administration also provides means to prevent the first metabolic passage through the liver, which in the case of meptazinol eliminates up to 98.1% of an oral dose. This high elimination of the drug in the first pass inevitably leads to great inter and intra subject variability in the plasma drug concentrations achieved. For example, in a publication (Norbury HM, Franklin, RA, Graham, DF, Eur. J. Clin. Pharm., Vol.25, pgs 77-80, (1983)) oral bioavailability varies from 1.89% to 18.5%, almost a range of ten times.

Intrinsically, meptazinol is not a potent medication when administered orally, referring doses of 200 mg every four to six hours. Even considering the low bioavailability of meptazinol, the average daily dose required for effective dosing would be ~ 50-100 mg, which is approximately a flow of ~ 83-166 μg / cm² / hour of a transdermal patch of 25 cm². These high flow rates are not usually seen with other transdermal products and this represents a significant technical challenge.

Examples of transdermal delivery systems that generally refer to opioid analgesics including meptazinol, for example, Oshlack and others (US Patent 6,716,449) have been indicated in this sector; Simon (Application for 50 US Patent published 2004-0024006); Klose et al. (US Patent Application 2004-0028625); Cassell (US Patent Application published 2006-0029654); Shevchuk et al. (US Patent Application published 2004-033253) and Schlagheck (US Patent Application published 2006-240128).

However, none of these references recognized the problem of the high flow rate associated only with meptazinol and focused on solving the problem of administering other types of opioid medications (Oschlack-morphine / hydromorphone, naltrexone, oxycodone / hydrocodone); Simon-nalmefene; Klose-fentanyl; Cassell-lidocaine; Shevchuk-naltrexone, fentanyl, oxycodone + opioid acyl antagonist; Schlagheck-opioid-N-methyl-D-aspartate antagonist). There is no evidence that any of these references 5 would solve the problem of administering meptazinol with the necessary flow rates nor are there explanations of how this problem could be solved.

Therefore, there is still a need in this sector for a transdermal delivery system for a mixed agonist-antagonist non-addictive analgesic such as meptazinol to achieve a sufficiently high flow rate to administer a pharmacologically effective amount of the medication to treat pain or for 10 provide analgesic relief.

The citation or identification of any document in the present patent application does not constitute admission that said document can be considered as prior art with respect to the present invention.

SUMMARY OF THE INVENTION

Surprisingly, applicants have discovered that some or all of the disadvantages of the prior art with respect to the use of meptazinol can be overcome by several delivery vehicles in a transdermal device (and very unexpectedly) with use of specific forms of meptazinol salts to provide sufficiently high flow rates to achieve effective plasma concentrations for analgesic relief.

Therefore, it is an objective of the present invention to disclose an administration system that avoids the first metabolic step 20 and facilitates a pharmacologically effective amount of meptazinol for pain relief or to provide analgesic relief. The invention discloses viable means to avoid the great first pass effect seen with meptazinol after oral dosing. The present invention will result in less variability in plasma concentrations, improved analgesic efficacy and better patient adaptation.

Patient adaptation will be further improved by the requirement of less frequent dosages due to the plasma concentrations maintained from this transdermal delivery device, in accordance with the present invention.

Additionally, the relatively slow increase in plasma concentration is expected to minimize the emetic effects of the drug that will once again contribute to minimizing variability in analgesically effective plasma drug concentrations and improving patient adaptation. 30

The terms "administration system" and "administration vehicle" that are used in this description are intended to describe a method for administering meptazinol by transdermal transport that avoids the "first metabolic step." The first metabolic step refers to the reduction of the bioavailability of a drug, for example, meptazinol, because of the metabolic or excreting capacity of the liver that is a common problem associated with oral administration. The transdermal administration is different from parenteral administration or by injection route because the latter derives the stratum corneum, epidermal and dermal layers of the skin and administers the active agent directly to the subcutaneous layer. The transdermal administration used in this description is intended to describe a process in which an active agent, for example, a form of meptazinol salt establishes contact and passes through or passes through permeation through one or more of the stratum corneum, epidermal layer and skin dermal This passage through crossing or permeation can be achieved by the following means, which are not limiting:

(1) transcellular penetration (through cells);

(2) intercellular penetration (between cells); O well

(3) transapendágica penetration (through hair follicles, sweat and sebaceous glands and pilosebaceous apparatus) 45

(4) predisposing the stratum corneum to allow the passage of the drug such as through the use of thermal ablation technologies.

(5) exploitation of natural transport mechanisms in the skin such as for phosphorylated vitamin E.

(6) facilitated passage through the upper layers of the skin using microneedles.

The invention disclosed is intended to comprise all pharmaceutically acceptable salts of meptazinol (including those that have a weakly acidic phenolic function and also those of weakly basic nitrogen acceptin). In addition, several other meptazinol precursors derived by covalent bond to phenolic function such as ethers, esters and glycosides are described below. Pharmaceutically acceptable salts (of phenol) include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as a calcium salt, magnesium salt and the like; organic amine salts such as triethylamine guanidine and N-substituted salts of guanidine, acetamidine and N-substituted acetamidine salts, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N salt '-dibenzylethylenediamine and the like. The salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate and the like are included among the pharmaceutically acceptable salts (of the acceptin); 10 salts of organic acids such as trifluoroacetate, maleate and the like; sulfonates, such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphor sulfonate and naphthalene sulfonate and the like; amino acid salts such as alaninate, asparginate, glutamate and the like.

Meptazinol is a chiral molecule that contains a stereogenic center in the C-3 position of the acepin and therefore can exist in two enantiomeric forms (stereoisomers R and S). fifteen

The reference to meptazinol for the purposes of this invention comprises any enantiomer and mixtures thereof including a racemic mixture (racemate) of the enantiomers, if not indicated otherwise.

These and other embodiments are disclosed or will be apparent and will be included in the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS 20

The following detailed description, which is exemplary, but is not intended to limit the invention exclusively to the specific embodiments described, can be better understood in conjunction with the accompanying drawings, in which:

Figure 1 shows the comparative permeation of the meptazinol free base and a series of its salts through the skin. 25

Figure 2 shows the flow through the skin of the different meptazinol salts through the human skin.

Figure 3 shows an example of a transdermal patch containing meptazinol.

Figure 4 shows the concentration time profile of the drug in plasma after repeated application of the patch to a "minipig" (laboratory pig).

DETAILED DECSRICPION 30

The present invention is directed to a delivery system that administers a pharmacologically effective amount of meptazinol for pain relief or to provide analgesic relief. Among the alternative examples of administration systems, without limiting it, are the means that enable the administration of meptazinol or a salt thereof by parenteral injection, pulmonary absorption, topical application, sublingual administration and rectal administration (by example, suppositories). Parenteral injection comprises administration by intravenous injection, subcutaneous injection, intramuscular injection, intraarterial injection and intrathecal injection. Pulmonary absorption includes the use of inhalants and aerosols. Topical administration includes the routes of administration: (1) mucous membranes that include without limitation conjunctive mucous membranes, nasopharynx, oropharynx, vagina, colon, urethra and urinary bladder; (2) the skin (which includes topical or transdermal administration); and (3) the eyes. 40

In one embodiment of the present invention, the administration vehicle is intended for topical administration to the skin and comprises a transdermal device that administers a pharmacologically effective amount of meptazinol for pain relief or to provide analgesic relief.

The transdermal device is intended to administer the pharmacologically effective amount of meptazinol, so that: (1) it controls the rate of administration of the medication to the skin or (2) it allows the skin to control the rate of absorption of the medication.

The transdermal device for transdermal administration of an effective amount of meptazinol to provide analgesic relief to a mammal or patient in need thereof comprises:

(i) a support layer;

(ii) a layer or container compartment;

(iii) a control membrane or an uncontrolled microporous membrane; Y

(iv) an adhesive film that is optionally applied as a perimetric ring or as a geometric model or combination of both; 5

(v) a separable coating; Y

 so that the container layer or compartment contains a compound comprising:

 (a) a form of meptazinol salt in an amount that results in the administration of an effective amount of meptazinol when added to the device and said device is applied to the skin; Y

 (b) a pharmaceutically effective carrier. 10

An example of the perimeter ring or geometric drawing is shown in Figure 4; that is, the adhesive film does not cover the entire surface of the control membrane; The adhesive film is applied to allow contact with the skin, while simultaneously allowing the control membrane or the microporous membrane without control to also establish contact with the skin.

In one embodiment, the container layer is a compartment and is formed from a control membrane or an uncontrolled microporous membrane and the support layer.

The support layer, the containing layer, the control membrane, the adhesive and separable coating can be formed using the conventional knowledge of the art, as disclosed in US Patent 6,818,226 (Dermal penetration devices and systems of administration of medications related thereto); US Patent 6,791,003 (System for transdermal administration of medicaments by dual adhesive); US Patent 6,787,149 (Topical application of opioid analgesic medications, such as morphine); US 6,716,446 (Controlled release compounds containing agonist and antagonist opioids); US Patent 5,858,393 (transdermal formulation); US Patent 5,612,382 (Composition for percutaneous absorption of pharmaceutically active ingredients); US Patent 5,464,387 (Transdermal Administration Device); US Patent 5,023,085 (Devices for transdermal flow in combination with iontophoresis in topical administration of pharmaceutical products); US Patent 4,891,377 (Transdermal Administration of Narcotic Narcotic Analgesics and Analogs); US Patent 4,654,209 (Preparation of percutaneous administration).

The transdermal device is capable of providing long-lasting relief and this is an improvement over the prior art that requires 4-6 doses per day. In one embodiment, the transdermal device is capable of providing up to about 8 hours of analgesic relief; In another embodiment, the transdermal device is capable of providing between 8 and 24 hours of relief and in another embodiment, the transdermal device is capable of providing from about 24 to 168 hours of relief.

Another embodiment of the transdermal device may constitute a so-called "adhesive medicine" or matrix patch in which there is no container layer, but instead the medication is intimately distributed in an appropriate pressure sensitive adhesive, such as HARD-polyacrylates. TAK without it being limiting. 35

In other embodiments of the invention, the transdermal device comprises a set of microfabricated microneedles in which the length of the microneedle or microneedles is sufficient to penetrate the stratum corneum (external part of 10-15 μm of the skin), but not It penetrates sufficiently to stimulate the nerves with greater depth in the skin. Henry et al., "Microfabricated Microneedles: A Novel Approach to Transdermal Drug Delivery", J. Pharm. Sci., Vol. 87: 922-925 (1998). The compound containing meptazinol is stored in the hollow part of the microneedle.

In another embodiment, the transdermal device consists of a removable patch with a series of metallic filaments and a separate electric actuator powered by battery. A momentary current pulse applied to the filaments through the activated one creates numerous microchannels through the stratum corneum that allow the subsequent permeation of the medication in a continuous manner. Four. Five

Another embodiment takes advantage of a natural transport mechanism in the skin to transport medications without interrupting the surface of the skin. This is based on the observation that phosphorylated vitamin E penetrates the skin almost ten times faster than vitamin E. The microencapsulation of the drug inside a vitamin envelope

E phosphorylated, creating nanospheres, enables the effective transport of the drug through the skin. Then continuous administration can be achieved over a prolonged period of time.

In other embodiments of the invention, transdermal administration of the medicament is favored by iontophoresis, magnetophoresis or sonophoresis. Iontophoresis involves the administration of charged chemical compounds through the skin's membrane using an applied electric field. See, for example, “Pharmaceutical Dosage Forms and 5 Drug Delivery Systems -Chapter 10– Transdermal Drug Delivery Systems, Ointments, Creams, Lotions and Other Preparations” (Chapter 10- Transdermal Administration Systems of medications, ointments, creams, lotions and other preparations), ed. by Ansel et al., Williams & Wilkins, page 360, (1995). Magnetophoresis involves the use of a magnetic field to favor the administration of the drug to the skin. See, for example, Murthy et al., "Physical and Chemical 10 Permeation Enhancers in Transdermal Delivery of Terbutaline Sulphate" (Means for promoting physical and chemical permeation in the transdermal administration of terbutaline sulfate), AAPS PharmSciTech. 2001; 2 (1). Sonophoresis is the use of high-frequency ultrasound and serves to alter the integrity of the stratum corneum layer and improve the permeability of compounds through the skin.

Given the low solubility of the free base form of the meptazinol free base (0.17 mg / ml in aqueous solution), it may be advantageous to derivatize meptazinol to form a precursor compound (or salt thereof) that will degrade into Meptazinol when it crosses the layer or layers of the skin. The transdermal administration of meptazinol can be achieved by a transdermal device that contains a precursor of meptazinol comprising, without limitation, meptazinol esters, glycosyros, meptazinol salts or mixtures thereof. Meptazinol precursors are compounds that undergo an in vivo transformation to produce meptazinol (for example, fractionation of an ester bond, glycolysis, formation of the free base from the salt). The esters of meptazinol, ethers and glycosiros can be compounds of formula (II):

wherein R is an acyl group, a mono, oligo or polysaccharide, or salts of mono, oligo or polysaccharides. (Oligosaccharides means a saccharide formed by 2-10 monosaccharide units linked together covalently). 25

When R forms an ester, R is a -C (= O) -C1-C12-alkyl; or R is -C (= O) -C1-C12-alkyl-NR1R2 in which R1 and R2 are independently hydrogen or C1-C4 alkyl; or R is C (= O) -C1-C12-alkylCO2R3 in which R3 is hydrogen; C1-C4 alkyl or a cation.

Alternatively, R is a -C (= O) -C1-C4-alkyl; or R is -C (= O) -C1-C4-alkyl-NR1R2 in which R1 and R2 are independently hydrogen or C1-C4 alkyl; or R is C (= O) -C1-C4-alkylCO2R3 in which R3 is hydrogen, C1-C4 alkyl or a cation.

When R forms an ether, R is a C1-C12-substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. Alternatively, R is a C1-C4 substituted or unsubstituted alkyl or a substituted or unsubstituted phenyl. In both embodiments, the substituents are selected from the group consisting of halogen C1-C4-alkyl and C1-C4 alkoxy.

When R is a monosaccharide, R is selected from the group consisting of erythrosil, treosil, ribosil, arabinosyl, xylosil, lixosil, allosil, altrosyl, glucosyl, glycosylamino, mannosyl, gulosyl, idosyl, galactosyl, galactosylamino, talosyl and salts thereof. themselves; or R is glucosyl, glycosylamino, galactosyl or galactosylamino and salts thereof; or R is glucosyl and salts thereof.

When R is an oligosaccharide, R is selected from the group consisting of lactose, sucrose, trehalose, trisaccharide Lewis a, 3'-O-sulfonate Lewis a, tetrasaccharide Lewis b, trisaccharide Lewis x, Sialyl Lewis x, 3'-O- Lewis x sulfonate, Lewis Lewis tetrasaccharide and and salts thereof.

When R is a polysaccharide, R is selected from the group consisting of chitin, chitosan, cyclodextrin, dextran and pullulan; or the cyclodextrin is -, - or -cyclodextrin; or the cyclodextrin is -cyclodextrin, dimethyl--cyclodextrin or hydroxypropyl--cyclodextrin.

Since cyclodextrin has a cavity that can receive the inclusion of a compound, such as meptazinol, the cyclodextrins in R above can also be added to meptazinol to form an inclusion complex instead of being covalently linked.

Alternatively, the precursor of meptazinol is a salt and R is hydrogen but absent, so that oxygen is negatively charged in which the salt form is selected from the group consisting of sodium, potassium, cesium, calcium salts , magnesium, N-substituted guanidine and guanidine salts and N-substituted acetamidine and acetamide, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine salts. Alternatively, R is hydrogen- or one of the above-mentioned substituents- and nitroacepin is positively charged and linked with hydrochloride, hydrobromide, sulfate, phosphate, format, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p -toluensulfonate, naphthalene sulphonate, camphor sulfonate, arginate, alaninate, asparginate, glutamate and mixtures thereof.

Surprisingly, and unlike in previous concepts that lower melting points (mp) are associated with better skin permeability, meptazinol accepine salts do not show this relationship. For example, meptazinol hydrochloride (mp 184 ° C) had a much better permeation capacity than maleate (mp 102-104 ° C). The hydrochloride also showed a higher flow rate than the camsylate (mp 46-48 ° C). fifteen

In addition and again in contrast to the previous concepts in this sector, additional unexpected results were obtained with the use of meptazinol salts for transdermal administration. Usually, the free base is the preferred form of a medicament for transdermal administration due to its greater lipophilicity. For example, the flow through the skin of a fentanyl free base is of the order of five times faster than the salt form. However, for meptazinol, the free base unexpectedly shows an unsatisfactory flow compared to the 20 different forms of salts. For example, meptazinol hydrochloride has a substantially greater flow than the free base. Previous reports in the scientific literature have suggested that ion pairs, that is, salts, can improve transdermal flow by virtue of beneficially increasing the physical-chemical characteristics of the molecule. These strategies have frequently used lipophilic counterions. Surprisingly, in the case of meptazinol, the use of more lipophilic counterions such as camsylate and tosylate were less effective in improving the flow than the use of salts of a stronger acid such as trifluoroacetic acid or hydrochloric acid.

Another factor that improves the overall flow rate through the skin was the unexpected radial or lateral diffusion of meptazinol; This is advantageous due to the fact that higher flows through the skin may allow smaller diameters of the patches.

An additional analgesic can be added to the transdermal device. Examples of analgesics 30, without limitation, include ethanol, non-asteroid anti-inflammatory drugs (NSAIDs) and other compounds with analgesic characteristics such as, without limitation, amitriptyline and carbamazepine.

In another embodiment of the invention, the only analgesic present in the composition in the container layer is a salt of meptazinol.

In another embodiment, the pharmaceutically effective carrier includes, but is not limited to, a solvent such as alcohol, isopropylmiristate, glycerol monooleate or a diol such as propylene glycol or the like. The administration of the salt form of meptazinol is favored by the use of a permeation increasing component that can also be included in the pharmaceutically effective carrier. Among the components that favor permeation and that are appropriate, without being limiting, polyunsaturated fatty acids (PUFA) such as arachidonic acid, lauric acid, -linoleic acid, linoleic acid and oleic acid; dimethylisosorbide; azones; 40 cyclopentadecalactone; alkyl-2- (N, N-aminodisubstituted) -alkanoate ester (NexAct); 2- (n-nonyl) -1,3-dioxaolane (SEPA); cod liver oil; essential oils, glycerol monoethers derived from saturated fatty alcohols; D-Limonene; menthol and menthol ethyl ether; N-methyl-2-pyrrolidone (NMP); phospholipids; squalene, terpenes; and alcohols such as methanol, ethanol, propanol and butanol. See for example. Pharmaceutical Skin Penetration Enhancement, ed. Walters et al., Marcel Dekker, Inc., (1993); Williams and others, "Penetration Enhancers" (Adv. Drug Deliv. Rev. Vol. 56, pages 603-618, (2004).

Alternatively, in another embodiment of the invention, transdermal administration of medications can be carried out using various ointments, creams, gels or lotions applied topically. Typically, these may comprise oil-in-water emulsions or water-in-oil emulsions by incorporating the meptazinol salt form into one of the preferred vehicles. Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions with an aqueous or oily base may be formulated and will generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents.

Transdermal administration of the medicament can be performed simultaneously with the oral administration of a compound containing an analgesic agent. 55

In another embodiment of the invention, the solubility (measured in aqueous solution) of a meptazinol salt is from 30 mg / ml to 500 mg / ml; In another embodiment of the invention, the solubility is from 50 mg / ml to 400 mg / ml; and in another additional embodiment of the invention, the solubility is from 75 mg / ml to 300 mg / ml.

The flow through the skin can be determined by multiplying the permeability coefficient (kp in cm / h) of meptazinol by the aqueous solubility of meptazinol. The aqueous solubility of meptazinol (free base) is 0.17 mg / ml 5 and the permeability coefficient of meptazinol can be calculated using the empirical form:

(MW for meptazinol is 233.35)

This results in an estimated flow through the skin of 5.6 μg / cm² / hour for meptazinol which is approximately 15-30 x lower than the flow necessary to achieve analgesic effects by transdermal administration. 10

In another embodiment of the invention, the flow through the skin for administration of the meptazinol salt form is 20 to 1000 μg / cm² / hour; In another embodiment of the invention, the flow through the skin for administration of meptazinol or precursor of meptazinol is 50 to 500 μg / cm² / hour; in another additional embodiment of the invention it is from 125 to 250 μg / cm² / hour and in another additional embodiment of the invention it is from 160 to 200 μg / cm² / hour.

In another embodiment of the invention, the pH of the environment in which the meptazinol salt is released is from pH 2.0 to 15 pH 4.0; in another embodiment it is pH 4.0 to pH 7.0; in another embodiment the pH is 4.0 to 6.0; and in a further embodiment the pH is 4.0 to 5.0.

Optionally, other skin care ingredients can be combined with the form of meptazinol salt due to the effects known in this sector; These include abrasives, absorbents, adhesives, anti-acne agents, anti-scab agents, anti-chare agents, anti-dandruff agents, anti-foaming agents, anti-fungal agents, 20 antimicrobial agents, antioxidants, antiperspirant agents, anti-static agents, binders, buffering agents, volume agents, agents chelants, dyes, callus / callus / wart removers, corrosion inhibitors, cosmetic astringent, cosmetic biocides, denaturing agents, depilating agents, medicating astringent, emollients, emulsion stabilizers, depilating agents, scrubs, external analgesics, film-forming agents, flavor, fragrance ingredients, gelling agents, humectants, lithic agents, occlusive opacifying agents, oxidizing agents, pesticides, pH adjusting agents, plasticizers, preservatives, propellants, reducing agents, skin bleaching agents, conditioning agents skin protectors skin, slip modifiers, solvents, sun protection agents, surface modifiers, surfactants (including cleaning agents, emulsifying agents, foam boosters, hydrotope, solubilizing agents, suspending agents), suspending agents (non-surfactants) , ultraviolet light absorbers, viscosity control agents, viscosity reducing agents, viscosity increasing agents (aqueous), viscosity increasing agents (non-aqueous) and mixtures thereof.

These additional skin care ingredients include without limitation those described in the International Cosmetic Ingredient Dictionary and Handbook, 9th edition (2002); Remington- The Science and Practice of Pharmacy, 21st edition (2005), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th edition (2005) and 35 Pharmaceutical Dosage Forms and Drug Delivery Systems by Ansel (8th edition), edited by Allen et al. , Lippincott Williams & Wilkins, (2005).

The control of the release rate of the meptazinol composition and avoiding compromising the stickiness of the perimeter ring of the adhesive layer of the transdermal device are also desirable characteristics. For this reason, in another embodiment a gelling agent is added to the meptazinol compound. Suitable gelling agents are included, without limitation, Klucel (hydroxypropyl cellulose) and Carbopol 980. These gelling agents, because of the viscosity they provide, control and restrict the speed of administration of the vehicle through the membrane microporous Typically this can be of the order of 1.5-3.0 uL / cm² / hour. Through this control of the speed of administration of the drug and the vehicle to the skin surface, this can serve to limit any unwanted skin irritation. Four. Five

One of the side effects of transdermal administration of an active agent is certainly the appearance of skin irritation. While the inventors do not wish to be limited by any theory, meptazinol can cause skin irritation due to the formation of oxidized or degraded products (for example, meptazinol 1,4 quinone, meptazinol dimers). In addition, the possibility of dimerization of this quinone could be responsible for the pronounced yellow discoloration of the gel that is observed at rest. It has been found that this discoloration can be totally eliminated by the inclusion of the antioxidant hydroxy toluene butylated (BHT-0.02-0.05%). Ascorbic acid (0.05%) also facilitates a certain reduction in this yellow discoloration, but other antioxidants such as butylated hydroxy anisole, alpha tocopherol and pyrogallol did not. Smaller amounts of BHT and ascorbic acid may also be suitable for the meptazinol compositions of the invention.

In this regard, another embodiment is a composition containing meptazinol for transdermal administration that is free of skin irritation which further comprises an antioxidant selected from the group consisting of BHT, ascorbic acid and mixtures thereof.

Another factor that could induce skin irritation could be partly an inappropriate pH, especially lower pH. This may be elevated by the use of pharmaceutically acceptable basifying agents, such as, without implying exclusive restriction, diethanolamine, disopropanolamine or tromethamine (TRIS).

In another embodiment of the invention, the use of the transdermal device described above can be used to provide analgesic effects to treat systemic or localized pain in a patient who requires it.

Another embodiment consists of a method of administration of meptazinol that avoids the first metabolic step, which comprises transdermal administration. In another embodiment of this invention, the method of administration is non-oral and non-parenteral.

Other advantages and features of the invention will become apparent upon reading the following description, provided by non-limiting examples.

Examples

Example 1 - Improved flow through the skin using meptazinol HCl salt. fifteen

Using human skin in a conventional Franz cell in an in vitro apparatus, transdermal permeation of meptazinol was measured by testing the amount of medication in the receiving fluid below the skin sample several times after application to the skin. Figure 1 shows that a salt of meptazinol is surprisingly more permeable than the free base of meptazinol. Figure 2 shows that surprisingly, meptazinol salts formed from a stronger acid such as a hydrochloride and a trifluoroacetate salt are absorbed more rapidly than those of weaker organic acids such as camsylate, tosylate or maleate.

The data presented in Table 1, below, show that under the conditions of the test that have been cited, the average flow for different salts tested were adequate to produce sufficient concentrations of meptazinol to produce a long-lasting effect when administered at a patient that requires it.

Table 1: Intersubject variability of flow rates for meptazinol salts through human skin 25

 Compound applied

 Cell ID Donor number Flow ug / cm² / hour Average flow standard deviation

 M HCl (1) M HCl (1) M HCl (1) M HCl (1) M HCl (1) M HCl (1)

 1 2 3 4 5 6 281 282 284 287 289 295 197.1 194.0 162.5 135.7 218.0 132.6 173.3 35.2

 M camsilate M camsilato M camsilato M camsilato M camsilato M camsilato

 7 8 9 10 11 12 281 282 284 287 289 295 78.1 110.9 27.3 45.1 204.2 9.5 79.2 71.2

 M tosylate M tosylate M tosylate M tosylate M tosylate M tosylate

 13 14 15 16 17 18 281 282 284 287 289 295 158.8 165.0 90.9 39.6 273.7 87.4 135.9 82.5

 M HCl (2) M HCl (2) M HCl (2) M HCl (2)

 19 20 21 22 292 288 282 281 66.5 222.6 213.4 213.4 179.0 75.1

 M TFA M TFA M TFA M TFA

 23 24 25 26 292 288 282 281 29.1 422.2 163.8 282.3 224.4 167.6

 M maleate M maleate M maleate M maleate

 27 28 29 30 292 288 282 281 41.3 91.3 85.3 93.9 78.0 24.7

Note.- The vehicle comprised 2% oleic acid; 2% dimethyl isosorbide and 96% propylene glycol.

The data in Table 2 were obtained using the same Franz cell technique in vitro verifying that surprisingly there was no correlation between lower melting points and higher solubilities with overall rates of flow through the skin. . For example, based on prior concepts in the art, it should be expected that meptazinol hydrochloride, which has a higher melting point than meptazinol free base, 5 had a less favorable flow rate through the skin but in instead it is several times better than the meptazinol free base. Similarly, meptazinol hydrochloride which is the salt of a stronger acid has lower solubility and a higher melting point than meptazinol camsylate, tosylate or maleate which is the salt of a weaker acid still having an unexpected Better flow rate through the skin.

Table 2: Saturated solubilities (and melting points) of meptazinol free base and selected salts in a potential delivery vehicle 10 comprising 2% oleic acid; 2% dimethyl isosorbide: 96% propylene glycol.

 Compound

 Solubility at 32ºC (mg / ml) MP (ºC)

 Meptazinol Hydrochloride Meptazinol Camsylate Meptazinol Tosylate Meptazinol Trifluoroacetate

 78 -250 ** -140 ** 170 * 184-186 46-48 40-42 112-114

 Meptazinol Maleate Meptazinol Free Base

 105 * -20 ** 102-104 128-133

* Measured by HPLC

** Estimated by visual appreciation only

Example 2 - Meptazinol Composition

Numerous studies were carried out using skin collected from cosmetic surgical processes in women (usually called "tummy tucks") to establish and refine the composition of the transdermal gel. These studies 5 culminated in the selection of a 3: 2: 95 vehicle weight ratio (OA: DI: PG) (OA-oleic acid; DI-dimethyl isosorbide; PG-propylene glycol).

A meptazinol gel composition for use with a transdermal patch was prepared by mixing together the following ingredients (all in% by weight):

83.296% Propylene glycol (PG) -EP (BASF and Inovene) 10

2.63% Oleic acid (OA) - Superfine oleic acid NF / EP (Croda)

1,754% Dimethyl Isosorbide (DI) -ArlasolveTM (Uniqema)

0.8% Hydroxypropyl cellulose-Klucel HF quality NF / EP (Hercules)

0.02% Butylated Hydroxytoluen (BHT) -EP quality (Fluka)

11.5% Maptazinol HCl BP quality (Kern Pharma) 15

Note: The weight ratio of (OA: DI: PG) in isolation is 3: 2: 95.

Example 4 - Transdermal patch containing meptazinol

Figure 4 shows an example of a transdermal patch containing meptazinol that has been prepared according to the invention.

The ScotchPak 9742 fluoropolymer with a thickness of 4.6 mils and a diameter of 98 mm was used to form a separable coating (1). DSM Solupor 10PO5A having a diameter of 55 mm was used with a 6 mm thermal sealing perimeter flange to form the microporous membrane (2). Amcor C (Amcor Flexibles Inc.) film with a thickness of 6 mils, 55 mm diameter and 6 mm perimeter thermal sealing flange (or alternatively 54 mm diameter with a 5 mm thermal sealing flange) was used. to form the support film (3). Dow Corning BIO PSA 7-4302 adhesive mixed with 2.5% Dow Corning 25 200 fluid (adhesion enhancer) was used to form the adhesive ring (4) having a diameter of 98 mm with a 50 mm center hole (coating weight of the adhesive ring (4) of 85 g / m²).

The medicine container is constituted by the combination of the microporous membrane (2) and the support film (3) and has a filling volume of 100 μl / cm². The meptazinol compound contained in the medicament container was 2.5 ml of the composition described in example 3. 30

Example 5 - In vivo transdermal absorption studies in "minipigs"

Two studies were carried out in “minipigs” of Göttingen leading to the daily application of the patch of example 4 up to a period of 7 days. This patch comprised a gel container (100 μl / cm², nominal initial volume 2.5 ml) on a microporous membrane of Solupor 10PO5A (surface area 25 cm²). It was fixed to the skin by an adhesive perimeter ring and an adhesive coating. On a separate occasion, the "minipigs" received an intravenous dose of meptazinol at ~ 1 mg / kg to enable bioavailability determination.

The results of this study showed that between 150-200 mg of medication left the patch over a period of 24 hours. The pharmacokinetic profile showed a negligible delay time and a maximum concentration time (tmax) that took place within 8 hours. Plasma levels were constantly maintained with an average fluctuation according to an index of 2.3 only. The transdermal bioavailability was low, of the order of 8% to 40

12%, possibly as a result of the metabolism in the skin of the "minipigs". However, such extensive glucuronidation has not been formed for other phenolic analgesics applied to human skin (Roy SD, Hou SY, Witham SL, Flynn GL, “Transdermal delivery of narcotic analgesics: comparative metabolism and permeability of human cadaver skin and hairless mouse skin ”(Transdermal administration of narcotic analgesics: comparative metabolism and permeability of human cadaver skin and hairless mouse skin), J Pharm Sci., vol. 83 (12): 1723-8 (1994)). 5

This surprising gain in the rate of flow through the skin was believed to be the result of rapid radial or lateral diffusion of the meptazinol salt when a gelling agent was added.

Example 6 - Protocol for determining flow through the skin in vivo in humans

The following protocol has to be practiced to determine the transdermal flow of a meptazinol gel formulation and to determine systemic bioavailability compared to an intravenous (IV) administration. 10 In addition, the protocol also allows the evaluation of the local safety and tolerance of the transdermal meptazinol gel compared to the IV (intravenous) administration of meptazinol and a placebo gel.

Treatment A: Meptazinol gel and / or a patch, as described in previous examples 3 and 4, will be applied and fixed inside the arm of ten volunteers with occlusion for 24 hours, in addition to a single simultaneous dose of intravenous placebo (sterile sodium chloride 0.9% weight / volume) 0.5 ml in injection infused over 15 of 30 seconds (slow IV injection). Meptazinol gel will be administered to provide a total topical dose of 129 mg of meptazinol (free base). The concentration of meptazinol hydrochloride in the gel will be 100 mg / ml; 0.1 ml / cm2 of the gel will cover a skin surface of 13 cm2. This will be contained within a stoma ring 4 cm in diameter, below which a microporous membrane DSM 10PO5A will be placed. The ring will be occluded with a clock crystal. twenty

Treatment B: A suitable placebo gel applied and fixed to the inside of the arm and occluded for 24 hours, in addition to a single simultaneous dose of 50 mg of meptazinol IV with 0.5 ml injection infused over 30 seconds (IV injection slow).

All individuals will receive both treatments over two dosage periods. Individuals will be randomized with respect to the sequence of treatments, selected to provide the appropriate assessment of safety, tolerance and pharmacokinetics.

This protocol is a randomized design with double crossing for a treatment sequence (AB or BA). The treatments will be administered on days 1 and 4 of the study. The gel (meptazinol or placebo formulation) will be applied to the skin and left for 24 hours. IV meptazinol or the appropriate IV placebo will be given as a slow bolus infusion in the opposite arm to the one receiving the gel. On day 1, the gel will be applied to the right arm, and on day 4 the gel will be applied to the left arm.

A series of plasma and urine (PK) samples will be collected and evaluated for gel tolerance during the study period.

This protocol will evaluate the concentration-time profiles of meptazinol (and possible metabolites) in plasma and pharmacokinetic parameters to include Cmax, tmax, AUC, t1 / 2 and bioavailability of meptazinol administered by transdermal gel with respect to intravenous administration for each individual ; estimation of transdermal flow; amount of meptazinol (and possible metabolites) excreted in the urine; local tolerance evaluated by visual inspection of the skin, erythema and edema, also checking the individual for itching, burning or other symptoms of discomfort at the place of application of the gel supported by digital photography of the place of application.

Claims (21)

1. Transdermal device for transdermal administration of an effective amount of meptazinol to provide analgesic relief to a mammal or patient in need thereof, comprising: (i) a support layer; (ii) a layer or container compartment; 5 (iii) a control membrane or an uncontrolled microporous membrane; (iv) an adhesive film that is optionally applied as a perimetric ring or as a geometric model or combination of both; (v) a separable coating; Y  so that the container layer or compartment contains a compound comprising 10 (a) a form of meptazinol salt in an amount that results in the administration of an effective amount of meptazinol when added to the device and said device is applied to the skin; Y (b) a pharmaceutically effective carrier. 2. Transdermal device according to claim 1, wherein the device further comprises a control membrane and an adhesive and optionally a removable coating. fifteen 3. A transdermal device according to claim 1, wherein the salt form is a hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, maleate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalene sulfonate, camfor sulfonate, alaninate , asparginate, glutamate or mixtures thereof. 4. A transdermal device according to claim 3, wherein the salt mixture is hydrochloride, camphor sulfonate, toluene sulfonate, trifluoroacetate, maleate or mixtures thereof. twenty 5. Transdermal device according to claim 4, wherein the meptazinol salt has a solubility selected from the group comprising from 30 mg / ml to 500 mg / ml; from 50 mg / ml to 400 mg / ml; and from 75 mg / ml to 300 mg / ml. 6. A transdermal device according to claim 4, wherein the meptazinol salt has a flow through the skin selected from the group consisting of 20 to 1000 μg / cm² / h; from 50 to 500 μg / cm² / h; from 125 to 250 μg / cm² / h and from 160 to 200 μg / cm² / h. 25 7. Transdermal device according to claim 4, wherein the meptazinol salt is released into the skin environment with a pH selected from the group consisting of pH 2 to pH 4.0; pH 4.0 to pH 7.0; pH 4.0 at pH 6.0 and pH 4.0 at pH 5.0. 8. A transdermal device according to claim 1, wherein it comprises a meptazinol salt in which the salt form is hydrochloride, trifluoroacetate or mixtures thereof, has a solubility of 75 mg / ml to 300 mg / ml and a flow through the skin of 75 to 250 μg / cm² / h. 30 9. Transdermal device according to claim 6, further comprising abrasives, absorbents, adhesives, anti-acne agents, anti-scab agents, anti-chare agents, anti-dandruff agents, anti-foaming agents, anti-fungal agents, anti-microbial agents, antioxidants, antiperspirants, anti-static agents, binders, buffering agents, bulking agents, chelating agents, dyes, corns / calluses / warts removers, corrosion inhibitors, cosmetic astringent, cosmetic biocides, denaturing, depilating agents, medicating astringent, emollients, emulsion stabilizers, depilating agents, exfoliants, external analgesics, film-forming agents, flavor agents, fragrance ingredients, humectants, lithic agents, occlusive opacifying agents, oxidizing agents, pesticides, pH adjusting agents, plasticizers, preservatives, propellants, reducing agents, bleaching agents skin age Skin conditioning, skin protectors, slip modifiers, solvents, sun protection agents, 40 surface modifiers, surfactants including cleaning agents, emulsifying agents, foam boosters, hydrotope, solubilizing agents, suspending agents , non-surfactant suspending agents, ultraviolet light absorbers, viscosity control agents, viscosity reducing agents, aqueous viscosity increasing agents, non-aqueous viscosity increasing agents and mixtures thereof. 10. A transdermal device according to claim 8, further comprising abrasives, absorbents, adhesives, anti-acne agents, anti-scab agents, anti-scale agents, anti-dandruff agents, anti-foaming agents, anti-fungal agents, anti-microbial agents, antioxidants, antiperspirants, anti-static agents, binders, buffering agents, bulking agents, chelating agents, dyes, corns / calluses / warts, corrosion inhibitors, cosmetic astringent, cosmetic biocides, denaturing, 5 depilating agents, medicating astringent, emollients, emulsion stabilizers, depilating agents, exfoliants, external analgesics, film-forming agents, flavor agents, fragrance ingredients, humectants, lithic agents, opacifying agents, occlusives, oxidizing agents, pesticides, pH adjusting agents, plasticizers, preservatives, propellants, reducing agents, bleaching agents the skin, ag skin conditioning entities, skin protectors, slip modifiers, solvents, sun protection agents, 10 surface modifiers, surfactants including cleaning agents, emulsifying agents, foam boosters, hydrotope, solubilizing agents, suspending agents , non-surfactant suspending agents, ultraviolet light absorbers, viscosity control agents, viscosity reducing agents, aqueous viscosity increasing agents, non-aqueous viscosity increasing agents and mixtures thereof. 11. Use of the transdermal device of claim 1 for the manufacture of a medical device to provide an analgesic effect to a patient in need. 12. Use according to claim 11, wherein the analgesic effect is localized. 13. Use according to claim 11, wherein the analgesic effect is systemic. 14. Use according to claim 11, wherein the administration of the transdermal device is accompanied by iontophoresis. twenty 15. Use according to claim 11, wherein the administration of the transdermal device is accompanied by magnetophoresis. 16. Use according to claim 11, wherein the administration of the transdermal device is accompanied by sonophoresis. 17. Use according to claim 11, wherein the transdermal administration is effected by using a lotion, cream or ointment instead of a device. 18. Use according to claim 11, wherein the transdermal administration is effected using a matrix type patch in which the medicament is dissolved in a suitable pressure sensitive adhesive. 19. Use according to claim 11, wherein the administration of the transdermal device is accompanied by thermal ablation. 30 20. Use according to claim 11, wherein the administration of the transdermal device is accompanied by a natural phosphorylated vitamin E skin transporter. 21. Use according to claim 11, wherein the administration of the transdermal device is accompanied by the use of microneedles.