CN101378737A - Transdermal delivery of meptazinol - Google Patents

Abstract

A delivery system for the delivery of a salt of meptazinol or meptazinol precursor which increases the bioavailability of meptanizol by an effective amount to provide analgesic relief is disclosed. One embodiment of the delivery system is a transdermal device which increases the skin flux of meptazinol by an effective amount to provide analgesic relief. Also disclosed are methods of providing analgesic relief.

Description

Transdermal administration of meptazinol

Related applications and incorporated by reference

United states provisional application 60/862,114 filed on 19.10.2006 and 60/753,357 filed on 21.12.2005, both entitled "transdermal administration of Meptazinol (Meptazinol)".

Any manufacturer's instructions, descriptions, product specifications, and product tables for any products mentioned in all documents cited or referenced herein ("herein cited documents"), in all documents cited or referenced in herein cited documents, and in any document incorporated herein or by reference herein, are incorporated herein by reference, and may be used in the practice of the present invention.

Technical Field

The present invention relates to the administration of a salt of meptazinol or a meptazinol precursor for analgesic purposes, and more particularly to a method and apparatus for the long term administration of meptazinol or a salt of a meptazinol precursor to a patient in need thereof at a substantially constant rate, while avoiding first pass metabolism.

Background

Inadequate pain relief has always represented a major problem for patients and healthcare workers. Optimal pharmacological management of pain requires the selection of an appropriate analgesic drug that can achieve rapid efficacy with minimal side effects.

Mild analgesics are readily available, and over-the-counter (OTC) analgesics such as acetaminophen are well documented in mild pain. Stronger analgesics, and often regular administration (a minimum of 3-4 times per day), have significant side effects, such as gastric bleeding and/or ulceration with non-steroidal anti-inflammatory drugs (NSAIDs); constipation is a significant side effect of mild opiates such as codeine and dihydrocodeine, while more potent prescription opiate analgesics such as tramadol, affect cognitive function and self-awareness in addition to gastrointestinal side effects.

Current treatment methods to treat moderate to severe pain are suboptimal. The most powerful analgesics, such as meperidine, fentanyl, morphine and diacetylmorphine, when used as suitable analgesics, also have well-known significant side effects that often limit their use, such as development of drug resistance over time, gastrointestinal side effects and respiratory depression. In addition, the use of the most powerful analgesics is strictly controlled due to their addictive nature.

Meptazinol is a mixed agonist-antagonist analgesic, having mu (mul) opioid receptor specificity, while exhibiting opioid and cholinergic properties, the chemical structure of which is defined as in formula (I):

the preparation of meptazinol hydrobromide is referred to in us 3,729,465 and the preparation of the free base form of meptazinol is referred to in us 4,197,241, both of which are incorporated by reference.

The cholinergic nature of meptazinol is believed to contribute to its general spectrum of anti-nociceptive effects and minimizing opioid side effects. Both the formal clinical study and the reported cases of street-less use/abuse indicate that meptazinol has a negligible propensity for clinical dependence. The non-addictive potential of meptazinol was first reported in 1987 by an internationally well-known researcher, dr. This property distinguishes meptazinol from many other strong analgesics, such as fentanyl (e.g., Duragesic), analgesic, oxycodone (e.g., Oxycontin, Percocet), which are classified as "controlled drugs" and are limited in subsequent prescription/dispensing, and morphine.

Meptazinol also has a number of clinical advantages over more conventional opioid analgesics, including causing minimal respiratory depression, causing minimal sedation, and no constipation effects.

Causing minimal respiratory depression makes meptazinol a favorable obstetric analgesic to avoid infant respiratory distress. Other analgesics given during labour, such as meperidine and diacetylmorphine, may cause significant respiratory depression in infants, leading to the so-called gray infant syndrome, which often requires the use of narcotic antagonists such as naloxone to reverse this effect.

Inducing minimal sedation is beneficial in the treatment of chronic pain conditions and may help patients perform normal daily life. Sedation associated with other analgesics often causes lethargy and a significant reduction in quality of life-bringing the patient into a near fuzzy state (twilight world).

The no constipation effect is an important property in the treatment of chronic pain. Constipation, often associated with other strong analgesics, is the most painful condition, especially for elderly patients. For this group of patients, often the target group for strong analgesics, the constipation-free effect of meptazinol represents an important advantage compared to other strong analgesics such as meperidine.

In addition, age is unlikely to affect meptazinol clearance by simple one-step glucuronidation (glucuronidation) processes, with filtration of a defined inactive water-soluble conjugate in the kidney. This step of conjugated metabolic clearance is not affected by age as are other clearance mechanisms such as direct filtration of active entities in the kidney or oxidative metabolic clearance as required by meperidine.

However, despite these clinical advantages, the use of meptazinol is limited by two major drawbacks (1) low oral bioavailability; the reported mean values, as a result of extensive first pass metabolism, are between 4-9%; and (2) nausea and vomiting tend to occur as with other strong analgesics. Nausea and vomiting worsen bioavailability due to the actual loss of drug with vomiting. Moreover, since meptazinol is known to inhibit gastric emptying and to effectively trap a portion of the oral dose of drug in the stomach, a greater amount of meptazinol may be lost through this vomiting.

All these factors lead to highly variable plasma drug levels of meptazinol after oral administration and subsequently variable patient responses. Because of the need to immediately relieve moderate to severe pain, patients may be reluctant to continue treatment with meptazinol unless the optimal dosage is found for their individual use. This frustration in achieving optimal dosage levels for each individual patient can lead to compliance issues, ineffective dosing, and pain relief. As a result of its short plasma half-life (1.5-2.0 hours), frequent oral administration of meptazinol is required, typically 4-6 times per day, which further exacerbates compliance issues.

Transdermal administration of strong analgesics has recently proven to be a useful alternative to injectable administration as a way to overcome many of the problems associated with their oral administration. Modulation of the typically seen sharp rise in plasma drug levels following oral administration can be used to reduce emesis associated with relatively high Cmax values from rapid absorption. In the specific case of meptazinol, avoidance of emesis becomes more important to reduce the loss of retained drug in the stomach by inhibiting gastric emptying.

Transdermal administration also provides a means of avoiding first-pass metabolism by the liver, which in the case of meptazinol, removes up to 98.1% of the oral dose. Such high first-pass clearance of the drug inevitably leads to large variability in the drug concentration reaching the plasma from patient to patient and within the patient. For example, in a publication (Norbury H.M, Franklin, R.A, Graham, D.F., Eur.J.Clin.pharm, Vol.25, pp.77-80, (1983)), oral bioavailability varies from 1.89% to 18.5%, almost 10-fold.

When administered orallyMeptazinol is not a potent drug in nature and requires a dose of 200mg every 4-6 hours. Even when the poor bioavailability of meptazinol is taken into account, the average daily required dose for an effective dose is-50-100 mg, which is close to that from 25cm²Transdermal patch of 83-166 mug/cm²Flux rate per hour. This inherently high flux rate is not common in other transdermal products and therefore represents a significant technical challenge.

Examples of transdermal drug delivery systems have been mentioned in the art, which generally refer to opioid analgesics including meptazinol, such as Oshlack et al (U.S. patent 6,716,449); simon (U.S. patent application publication 2004-0024006); klose et al (U.S. patent application publication 2004-0028625); cassell (U.S. patent application publication 2006 + 0029654); shevchuk et al (U.S. patent application publication 2004-.

However, none of these references recognize the high flux rate problem associated with meptazinol alone, nor address the problem of administering other types of opioids (Oschlack-morphine/hydromorphone, naltrexone, oxycodone/hydrocodone, Simon-nalmefene, Klose-fentanyl, Cassell-lidocaine, Shevchuk-naltrexone, fentanyl, oxycodone + acyl opioid antagonists, Schlagheck-opioid-N-methyl-D-aspartate antagonists). There is no evidence that any of these references addresses the problem of administering meptazinol at the desired high-throughput rate, or any discussion of how to address this problem.

Thus, there remains a need in the art for transdermal drug delivery systems for non-addictive mixed agonist-antagonist analgesics, such as meptazinol, to achieve a sufficiently high flux rate to administer a pharmacologically effective amount of the drug to treat pain or provide analgesic relief.

Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.

Disclosure of Invention

Surprisingly, applicants have found that some or all of the disadvantages associated with the use of meptazinol in the art can be overcome by utilizing the specific salt form of meptazinol with various delivery vehicles (and most unexpectedly) in a transdermal device to provide a sufficiently high flux rate to achieve plasma concentrations effective for analgesic relief.

It is therefore an object of the present invention to provide a delivery system that avoids first pass metabolism and delivers a pharmacologically effective amount of meptazinol for treating pain or providing analgesic relief. The present invention provides a viable approach to avoid the very large first-pass effect seen after oral administration of meptazinol. The present invention will result in low variability in reaching plasma concentrations, enhanced analgesic effect and improved patient compliance.

By requiring less frequent dosing, patient compliance will be further improved due to the sustained plasma concentrations achieved from such transdermal delivery devices according to the present invention.

In addition, a relatively slow rise in plasma drug concentration is expected to minimize the emetic effect of the drug, which in turn helps to minimize variability in the concentration of the analgesic-effective plasma drug and improves patient compliance.

The terms "delivery system" and "delivery vehicle" as used herein are meant to describe a method of providing meptazinol via transdermal delivery that avoids "first pass metabolism". First pass metabolism refers to a decrease in bioavailability of a drug such as meptazinol due to the metabolic or excretory capacity of the liver, which is a common problem associated with oral administration. Transdermal administration is distinguished from parenteral or injection administration, which bypasses the stratum corneum, epidermis and dermis layers of the skin and delivers active agents directly into the subcutaneous layer. Transdermal as used herein is meant to describe a process wherein an active agent such as meptazinol or a derivative or precursor thereof contacts and passes or permeates through one or more of the stratum corneum, epidermis and dermis layers of the skin. Such passage or permeation may be accomplished by, for example, but not limited to, the following methods:

(1) transcellular penetration (across cells);

(2) intracellular infiltration (between cells); or

(3) Penetration (through the hair follicles, sweat and sebaceous glands and the pilosebaceous apparatus) via the adnexa (transappendagel);

(4) passing the drug through by pre-treating the stratum corneum, such as with thermal ablation techniques;

(5) use of natural transport mechanisms in the skin such as those used to phosphorylate vitamin E;

(6) passage through the uppermost layer of skin is facilitated by a micro-needle.

The invention disclosed herein is meant to include all pharmaceutically acceptable salts of meptazinol (including those with weakly acidic phenolic function as well as those with weakly basic azepine nitrogen function). And, it includes various other meptazinol precursors derived from the functional bonding of phenols such as ethers, esters and glucosides as described below by covalent bonds. Pharmaceutically acceptable (phenolic) salts include, but are not limited to, metal salts such as sodium, potassium, cesium and the like; alkaline earth metals such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine guanidine & N-substituted guanidine salt, acetamidine & N-substituted acetamidine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt and the like. Pharmaceutically acceptable (azepine) salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as trifluoroacetate, maleate, and the like; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, naphthalenesulfonate and the like; amino acid salts such as alanine salts, asparagine salts, glutamate salts and the like.

Meptazinol is a chiral molecule containing a stereogenic center at the C-3 position of azepine and can therefore exist in two enantiomeric forms (R and S stereoisomers).

Unless otherwise indicated, reference to meptazinol for the purposes of the present invention includes each enantiomer and mixtures thereof, including racemic mixtures (racemates) of the enantiomers.

It is noted that in this disclosure, and in the claims and/or paragraphs particularly, terms such as "comprises" and the like, have the meaning dictated by U.S. patent law, e.g., they mean "comprises" and the like; terms such as "consisting essentially of" have the meaning prescribed in U.S. patent law, e.g., they allow for elements not explicitly recited; but excludes elements found in the prior art or that may affect the essential characteristics or novelty of the invention.

It is further noted that the present invention is not intended to include any previously disclosed product, process for making the product, or method of using the product within the scope of the present invention, which satisfies the written description and enforceable requirements (enablement requirements) of USPTO (35 u.s.c.112, first paragraph) or EPO (EPC, clause 83), and accordingly the applicant reserves the right, and a disclaimer of any previously disclosed product, process for making the product, or process for using the product is disclosed herein.

These and other embodiments are disclosed in, or are apparent from and encompassed by, the following detailed description.

Drawings

The following detailed description, given by way of example and not intended to limit the invention solely to the specific embodiments described, may best be understood by reference to the accompanying drawings, in which:

figure 1 illustrates a comparison of penetration of meptazinol free base and some of its salts through human skin.

Figure 2 shows the skin flux of various salts of meptazinol through human skin.

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

Figure 4 shows a time plot of plasma drug concentration after repeated patch applications to mini-pigs.

Detailed description of the preferred embodiments

The present invention relates to a delivery system for the administration of a pharmacologically effective amount of meptazinol for the treatment of pain or for providing analgesic relief. Examples of alternative delivery systems include, but are not limited to, those capable of administering meptazinol or its salt forms by parenteral injection, pulmonary absorption, topical administration, sublingual administration, and rectal administration (e.g., suppositories). Parenteral injection includes administration by intravenous, subcutaneous, intramuscular, intraarterial, and intrathecal injection. Pulmonary absorption includes the use of inhalants and aerosols. Topical administration includes administration through (1) mucosa, including but not limited to mucosa of conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and bladder; (2) skin (including topical or transdermal administration); and (3) the eye.

In one embodiment of the invention, the delivery vehicle is for topical administration to the skin and includes, but is not limited to, a transdermal device, gel, cream, lotion, or ointment that delivers a pharmacologically effective amount of meptazinol for treating pain or providing analgesic relief.

In another embodiment of the invention, the delivery vehicle is a transdermal device. Transdermal devices are intended to administer a pharmacologically effective amount of meptazinol by one of (1) controlling the rate of administration to the skin or (2) allowing the skin to control the rate of drug absorption.

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

(i) a bottom layer (backing layer);

(ii) reservoir (reservoir layer) or barrier;

(iii) a control film or a non-control microporous film; and

(iv) an adhesive film, optionally applied as a peripheral ring (permeter ring) or as a geometric figure or a combination thereof;

(v) a release liner; and

wherein the reservoir or compartment comprises a composition; the composition comprises

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

(b) a pharmaceutically effective carrier.

Examples of peripheral rings (permeter rings) or geometric patterns are shown in fig. 4, i.e., the adhesive film does not cover the entire surface area of the control film; the adhesive film is applied so that it can be in contact with the skin while also allowing the control film or the non-control microporous film to be in contact with the skin.

In one embodiment of the invention, the reservoir is a barrier layer formed from a controlling or non-controlling microporous membrane and a bottom layer.

The base layer, reservoir, control membrane, adhesive film and release liner may be formed using conventional teachings in the art, such as those referred to in U.S. Pat. No. 6,818,226 (German industries and drug delivery systems incorporation same); U.S. Pat. No. 5,6,791,003 (Dual adaptive drive delivery system); U.S. Pat. No. 6,787,149 (Topicapplication of opioid analytical drugs such as morphine); U.S. Pat. No. 5,6,716,449 (Controlled release compositions containing opioidaconist and antaconist); us patent 5,858,393 (transdermalform); U.S. Pat. No. 5,612,382(Composition for continuous active of pharmaceutical ingredients); U.S. Pat. No. 5, 5,464,387(Transdermal delivery device); U.S. Pat. No. 5,023,085(Transdermal fluorides in compositions with atomic administration of pharmaceuticals); U.S. Pat. No. 4,891,377(Transdermal delivery of the scientific and analytical methods and analogues); U.S. Pat. No. 4,654,209(Preparation of cosmetic administration), each of which is incorporated by reference.

The transdermal devices of the present invention are capable of providing long lasting relief, an improvement over the prior art requiring 4-6 doses per day. One embodiment of the transdermal device is capable of providing analgesic relief for up to about 8 hours; in another embodiment of the present invention, the transdermal devices are capable of providing relief for about 8 to about 24 hours; in a further embodiment of the present invention, the transdermal device is capable of providing relief for about 24 hours to about 168 hours.

Another embodiment of a transdermal device may constitute a so-called "drug in adhesive" or matrix patch, where there is no reservoir, but instead the drug is intimately distributed on a suitable pressure sensitive adhesive, such as, but not limited to, DURO-TAK polyacrylate.

In yet another embodiment of the present invention, the transdermal device comprises an array of micro-assembled micro-needles, wherein the micro-needles are long enough to penetrate the stratum corneum (10-15 μm outside the skin) but short enough not to stimulate nerves deep in the skin. Henry et al, "Microfibrous Microneedles: A Novel approach to Transdermal Drug Delivery", J.Pharm, Sci., Vol.87, 922 925 (1998). The composition containing meptazinol was stored in the hollow of a micromanipulator needle.

In a further embodiment of the invention, the transdermal device is comprised of a disposable patch having an array of wires and a separate electrokinetic electroactive agent. The momentary pulse of current applied to the filament by the activator creates numerous micro-channels through the stratum corneum, allowing the drug to subsequently permeate in a continuous manner.

Further embodiments use natural delivery mechanisms in the skin to carry the drug through without damaging the skin surface. This is based on the observation that phosphorylated vitamin E permeates the skin almost 10 times faster than vitamin E itself. Microencapsulation of the drug within the phosphorylated vitamin E shell creates nanospheres that then allow for efficient transport of the drug across the skin. Thereby achieving long-term continuous administration.

In another embodiment of the invention, transdermal administration is enhanced by iontophoresis, magnetophoresis (magnetophoresis) or sonophoresis (sonophoresis). Iontophoresis involves the administration of charged compounds through the skin using an applied electric field, as described, for example, in "Pharmaceutical document Forms and Drug Delivery Systems-Chapter 10-Transdermal Drug Delivery Systems, maintenance, Creams, localities and Other Preparations", Ansel et al, Williams & Wilkins, p.360, (1995). Magnetophoresis (magnetophoresis) includes drug administration enhanced to the skin using a magnetic field, see, e.g., Murthy et al, "Physical and Chemical approval Enhancersin TransdermalelDelivery of Terbutaine Sulphate", AAPS PharmScitech.2001; 2(1)). Sonophoresis (sonophoresis) utilizes high frequency ultrasound waves that are used to compromise the integrity of the stratum corneum and to increase the permeability of compounds through the skin.

Due to the low solubility of the free base form of meptazinol as the free base (0.17 mg/ml in aqueous solution), it is advantageous to derivatize meptazinol to form a precursor compound (or salt thereof) that will degrade into meptazinol as it passes through the skin layers. Thus, another embodiment of the present invention is the transdermal administration of meptazinol via a transdermal device containing a meptazinol precursor including, but not limited to, meptazinol ester, meptazinol glucoside, meptazinol salts or mixtures thereof. The meptazinol precursor is a compound that undergoes in vivo conversion to yield meptazinol (e.g., cleavage of ester bonds, glycolysis, formation of free base from salt). The meptazinol esters, ethers and glucosides of the invention are compounds of formula (II):

wherein R is acyl, monosaccharide, oligosaccharide or polysaccharide, or salt of monosaccharide, oligosaccharide or polysaccharide. (an oligosaccharide for the purposes of the present invention means a saccharide comprising 2-10 monosaccharide units covalently bonded together).

When R forms an ester, one embodiment of the present invention is that R is-C (═ O) -C₁-C₁₂-an alkyl group; yet another embodiment is where R is-C (═ O) -C₁-C₁₂-alkyl-NR₁R₂Wherein R is₁And R₂Independently is hydrogen or C₁-C₄An alkyl group; yet another embodiment is where R is C (═ O) -C₁-C₁₂-alkyl CO₂R₃Wherein R is₃Is hydrogen, C₁-C₄Alkyl or is a cation.

In a further embodiment of the invention, R is-C (═ O) -C₁-C₄-an alkyl group; yet another embodiment is where R is-C (═ O) -C₁-C₄-alkyl-NR₁R₂Wherein R is₁And R₂Independently is hydrogen or C₁-C₄An alkyl group; yet another embodiment is where R is C (═ O) -C₁-C₄-alkyl CO₂R₃Wherein R is₃Is hydrogen, C₁-C₄Alkyl or is a cation.

When R forms an ether, one embodiment of the present invention is that R is substituted or unsubstituted C₁-C₁₂-an alkyl group, or a substituted or unsubstituted aryl group. In another embodiment where R is an ether, R is substituted or unsubstituted C₁-C₄-alkyl, or substituted or unsubstituted phenyl. In two embodiments, the substituents are selected from the group consisting of halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy groups.

When R is a monosaccharide, one embodiment of the invention is that R is selected from the group consisting of erythrosyl (erythrosyl), threonyl (threonyl), ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrose, glucosyl, glucosylamino, mannosyl, gulose, idosyl, galactosyl, galactosylamino, talose and salts thereof; another embodiment is R is glucosyl, glucosylamino, galactosyl or galactosylamino and salts thereof; yet another embodiment of the invention is where R is glucosyl and salts thereof.

When R is an oligosaccharide, one embodiment of the invention is that R is selected from the group consisting of lactose, sucrose, trehalose, Lewis a trisaccharide, 3 '-O-sulfonic acid Lewis a, Lewis b tetrasaccharide, Lewis x trisaccharide, sialylated Lewis x, 3' -O-sulfonic acid Lewis x, Lewis y tetrasaccharide and salts thereof.

When R is a polysaccharide, one embodiment of the invention is where R is selected from the group consisting of chitin, chitosan, cyclodextrin, dextran, and pullulan, and another embodiment of the invention is where the cyclodextrin is alpha-, beta-, or gamma-cyclodextrin; yet another embodiment of the invention is where the cyclodextrin is beta-cyclodextrin, dimethyl beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin.

Since cyclodextrins have a cavity which can accommodate inclusion bodies of compounds such as meptazinol, another embodiment of the present invention is that cyclodextrins described in R above can also be added to meptazinol to form inclusion complexes, rather than covalent linkages.

In another embodiment of the invention, where the meptazinol precursor is a salt and R is hydrogen but absent, whereby oxygen is negatively charged, an embodiment of the invention is where the salt form is selected from the group consisting of sodium, potassium, cesium, calcium, magnesium, guanidine & N-substituted guanidine and acetamidine & N-substituted acetamidine triethylamine, pyridinium, picolinium, ethanolamine, triethanolamine, dicyclohexylamine, N' -dibenzylethylenediamine. Another embodiment of the invention is when R is hydrogen or one of the above substituents, the nitrogen of the azepine is positively charged and is associated with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, arginine, alanine, asparagine, glutamate and mixtures thereof.

Surprisingly, contrary to prior art concepts that lower melting points (mp) are generally associated with increased skin penetration, the azepine salts of meptazinol do not show such a relationship. For example, meptazinol hydrochloride (mp 184 ℃ C.) is much more permeable than meptazinol maleate (mp 102 ℃ C.) and 104 ℃ C. The hydrochloride salt also showed higher flux rates than the camphorsulfonate salt (mp 46-48 deg.C).

Further, again contrary to prior art concepts, additional unexpected results occurred when meptazinol salts were used for transdermal administration. Due to its greater lipophilicity, the free base is generally the preferred form of drug for transdermal administration. For example, fentanyl free base has a skin flux up to five times faster than the salt form. However, the free base showed unexpectedly poor flux for meptazinol compared to its various salt forms. For example, meptazinol hydrochloride has a significantly greater flux than the free base. It has been shown in prior reports of the scientific literature that ion pairs, i.e., salts, can enhance transdermal flux due to their beneficial effect in enhancing the physicochemical properties of the molecule. This strategy typically uses lipophilic counterions. Surprisingly, the use of more lipophilic counterions such as camphorsulfonate, tosylate is less effective at increasing flux than the use of salts of stronger acids such as trifluoroacetic acid or hydrochloric acid in the case of meptazinol.

A further factor that improves the overall skin flux rate is the unexpected radial or lateral diffusion of meptazinol; this is advantageous because higher skin flux may allow for smaller diameter patch sizes.

In another embodiment of the invention, additional analgesics may be added to the transdermal device. Examples of analgesics include, but are not limited to, ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), and other compounds with analgesic properties, such as, but not limited to, amitriptyline (amitriptyline) and carbamazepine (carbamazepine).

In another embodiment of the invention, the only analgesic present in the composition in the reservoir is a salt of meptazinol or a salt of a meptazinol precursor.

In another embodiment of the invention, pharmaceutically effective carriers include, but are not limited to, solvents such as alcohols, isopropyl myristate, glycerol monooleate, or glycols such as propylene glycol, or analogs thereof. The administration of meptazinol or a meptazinol precursor (or salt thereof) is enhanced by the use of a penetration enhancer, which may also be included in the pharmaceutically effective carrier. In one embodiment of the present invention, suitable penetration enhancers include, but are not limited to, polyunsaturated fatty acids (PUFAs), such as arachidonic acid, lauric acid, alpha-linolenic acid, linoleic acid, and oleic acid; dimethyl isosorbide; (ii) azone; cyclopentadecanolide (cyclopentadieneacetone); alkyl-2- (N, N disubstituted amino) -alkanoate (NexAct); 2- (n-nonyl) -1, 3-dioxolane (dioxalane) (SEPA); cod liver oil; extracting oil (essential oil), glycerol monoethers derived from saturated fatty alcohols; d-limonene (limonene); menthol and menthol ethyl ether; n-methyl-2-pyrrolidone (NMP); a phospholipid; squalene; a terpene; alcohols such as methanol, ethanol, propanol and butanol. See, e.g., Pharmaceutical Skin pennetration enhancement, Walters et al, eds; marcel Dekker, inc., (1993); williams et al, "Pentation Enhancers", adv.drug.Deliv.Rev., Vol.56, p.603-618, (2004).

Alternatively, transdermal drug delivery in another embodiment of the present invention may be accomplished with various topical ointments, creams, gels, or lotions. Typically these may comprise an oil-in-water emulsion or a water-in-oil emulsion incorporating meptazinol or a meptazinol precursor in one of the preferred excipients. For example, ointments and creams may be formulated with an aqueous or oil base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

In another embodiment of the invention, transdermal drug administration is accompanied by oral administration of a composition containing an analgesic agent.

In another embodiment of the invention, the solubility (measured in aqueous solution) of meptazinol or a meptazinol precursor or salt thereof is from about 30mg/mL to about 500 mg/mL; yet in another embodiment of the invention, the solubility is from about 50mg/mL to about 400 mg/mL; in still further embodiments of the present invention, the solubility is from about 75mg/mL to about 300 mg/mL.

Skin flux can be determined by multiplying the permeability coefficient (kp, in cm/h) of meptazinol by the water solubility of meptazinol. The water solubility of meptazinol (free base) is 0.17mg/mL, and the permeability coefficient of meptazinol can be calculated by the following empirical formula:

lo gk_pthis resulted in an estimated skin flux of meptazinol of only 5.6 μ g/cm, as high as-2.7 +0.71 log P-0.0061MW (meptazinol MW 233.35)²This is about 15-30x lower than the flux rate necessary to achieve analgesic effect by transdermal administration.

In another embodiment of the invention, the skin flux for administration of meptazinol or a meptazinol precursor or salt thereof is from about 20 to about 1000 μ g/cm²H; yet in another embodiment of the invention, the skin flux for administration of meptazinol or a meptazinol precursor is from about 50 to about 500 μ g/cm²H; in a further embodiment of the invention from about 125 to about 250. mu.g/cm²H, in a still further embodiment of the invention, from about 160 to about 200. mu.g/cm²/h。

In another embodiment of the invention, the pH of the environment at which meptazinol or a meptazinol precursor or salt thereof is released is from pH2.0 to about pH 4.0; from about pH4.0 to about pH7.0 in yet another embodiment; and in yet another embodiment, the pH is from about 4.0 to about 6.0; in a further embodiment, the pH is from about 4.0 to about 5.0.

Optionally, additional skin care ingredients may be used in combination with meptazinol or a meptazinol precursor or salt thereof for effects already recognized in the art to which they pertain. These ingredients include abrasives, absorbents, binders, anti-acne agents, anti-caking agents, anti-caries agents, antidandruff agents, antifoaming agents, antifungal agents, antimicrobial agents, antioxidants, antiperspirants, antistatic agents, binders, buffering agents, fillers, chelating agents, colorants, exfoliants/callosum/verruca removal agents, preservatives (corrusion inhibitors), cosmetic astringents, cosmetic biocides, denaturants, depilatories (depigmenting agents), drug astringents, emollients, emulsion stabilizers, depilatories (exfoliating agents), exfoliants, external analgesics, film formers, flavors, aroma components, gelling agents, humectants, lysing agents, occlusive opacifiers, oxidizing agents, insecticides, pH adjusters, plasticizers, preservatives (preservatives), propellants, reducing agents, skin whitening agents, skin conditioning agents, skin protectants, anti-acne agents, anti-dandruff agents, cosmetic astringents, cosmetic agents, skin lightening, Slip modifiers (slip modifiers), solvents, sunscreens, surface modifiers, surfactants (including detergents, emulsifiers, foam boosters, hydrotropes, solubilizers, suspending agents), suspending agents (non-surfactants), uv absorbers, viscosity control agents, viscosity reducers, viscosity boosters (aqueous), viscosity boosters (non-aqueous), and mixtures thereof.

Such additional skin care ingredients include, but are not limited to, those described in The International Cosmetic Ingredient Dictionary and handbook, 9 th edition (2002); Remington-The Science and Practice of pharmacy, 21 st edition (2005), The pharmaceutical Basis of Therapeutics, Goodman & Gilman, 11 th edition (2005), and The commercial vehicle Forms and Drug Delivery Systems of Ansel (8 th edition), Allen et al, eds., Lippincott Williams & Wilkins, (2005).

And also needs to controlThe release rate of the meptazinol composition is made and the stickiness of the peripheral ring (permeter ring) of the adhesive film of the transdermal device is avoided from being impaired. Thus another embodiment of the present invention is the addition of a gelling agent to the meptazinol composition. Suitable gelling agents include, but are not limited to, Klucel (hydroxypropyl cellulose) and Carbopol 980. These gelling agents, due to the viscosity they provide, will control and limit the rate of excipient administration through the microporous membrane. Typically it is about 1.5-3.0. mu.L/cm²H is used as the reference value. By thus controlling the rate of administration of the drug and excipients to the skin surface, it may be useful to limit any unwanted skin irritation.

One of the side effects of transdermal delivery of active agents is indeed the occurrence of skin irritation. While not wishing to be bound by theory, meptazinol may cause skin irritation due to the formation of oxidation or degradation products (e.g., meptazinol 1, 4 quinone, meptazinol dimer). Furthermore, this dimerization possibility of quinones leads to a pronounced yellow discoloration of the gel observed after standing. It has been found that this discoloration can be completely eliminated by incorporating the antioxidant butylated hydroxytoluene (BHT-0.02-0.05%). Ascorbic acid (0.05%) may also provide some reduction of this yellow discoloration, but other antioxidants such as butylated hydroxyanisole, alpha tocopherol and pyrogallol cannot. Lesser amounts of BHT and ascorbic acid are also suitable for use in the meptazinol compositions of the present invention.

Likewise, another embodiment of the present invention is a composition for transdermal administration without skin irritation comprising meptazinol, further comprising an antioxidant selected from the group consisting of BHT, ascorbic acid and mixtures thereof.

Another factor that may cause skin irritation may be in part an inappropriate pH, particularly a low pH. This can be improved by using a pharmaceutically acceptable alkalizing agent such as, but not limited to, diethanolamine, diisopropanolamine or Tromethamine (TRIS).

In another embodiment of the invention, the use of a transdermal device as described above can be used to provide an analgesic effect to treat systemic or local pain in a patient in need thereof.

Yet another embodiment of the invention is a method of administering meptazinol that avoids first pass metabolism and includes transdermal administration. In another embodiment of the invention, the method of administration is non-oral and/or non-parenteral.

Further advantages and characteristics of the invention will become apparent upon reading the following description, given by way of non-limiting example.

Examples

Example 1 skin flux enhancement by Using Meptazinol hydrochloride

Transdermal penetration of meptazinol was measured in a conventional Franz cell in vitro device using human skin by determining the amount of drug in the recipient fluid under skin samples at different times after application to the skin. Figure 1 shows that the meptazinol salt is surprisingly more permeable than the free base form of meptazinol. Figure 2 shows that meptazinol salts such as hydrochloride and trifluoroacetate salts formed from strong acids are surprisingly absorbed more rapidly than those formed from weaker organic acids such as camphorsulfonate, tosylate or maleate salts.

The data shown in table 1 below show that under the test conditions listed above, the average flux of the various salts detected is suitable to produce a meptazinol concentration sufficient to cause a long lasting effect when administered to a patient in need thereof.

TABLE 1 interpersonal variability of meptazinol salt flux rate through human skin

Compounds for administration	Diffusion cell ID	Donor numbering	Flux μ g/cm2/h	Mean flux. + -. sd
					M HCl(1)M HCl(1)M HCl(1)M HCl(1)M HCl(1)M HCl(1)	123456	281282284287289295	197.1194.0162.5135.7218.0132.6	173.3±35.2
M Camphorsulfonate	789101112	281282284287289295	78.1110.927.345.1204.29.5	79.2±71.2
					M tosylate	131415161718	281282284287289295	158.8165.090.939.6273.787.4	135.9±82.5
M HCl(2)M HCl(2)M HCl(2)M HCl(2)	19202122	292288282281	66.5222.6213.4213.4	179.0±75.1
					M TFAM TFAM TFAM TFA	23242526	292288282281	29.1422.2163.8282.3	224.4±167.6
M maleate	27282930	292288282281	41.391.385.393.9	78.0±24.7

NB excipient 2% oleic acid 2% dimethylisosorbide 96% propylene glycol

The data in table 2 were obtained using the same in vitro Franz cell technique, which demonstrates that there is surprisingly no correlation between lower melting point and higher solubility with total skin flux rate. For example, based on current opinion in the art, meptazinol hydrochloride having a higher melting point than meptazinol free base has been expected to have poorer skin flux rates, but instead several times better than meptazinol free base. Also, the strong acid salt meptazinol hydrochloride has a lower solubility and a higher melting point than the weak acid salt meptazinol camphorsulfonate, tosylate or maleate, but still has unexpectedly better skin flux rates.

Table 2 saturation solubility (and melting point) of meptazinol free base and selected salts in a potential dosing vehicle containing 2% oleic acid, 2% dimethyl isosorbide, 96% propylene glycol.

Compound (I)	Solubility at 32 ℃ (mg/ml)	Melting Point (. degree.C.)
			Meptazinol hydrochloride Meptazinol Camphol Meptaol tosylate Meptaol Trimethol Trifluoroacetate Meptaol maleate Meptaol free base	78～250＊＊～140＊＊170＊105＊～20＊＊	184-18646-4840-42112-114102-104128-133

^＊Measurement by HPLC

^＊＊Evaluation by visual assessment alone

Example 2 Meptazinol compositions

Many studies were conducted to identify and refine transdermal gel compositions using skin collected from female cosmetic surgery procedures (usually "tight abdomen"). These studies peaked when a 3:2:95 (OA: DI: PG) excipient (OA-oleic acid; DI-dimethylisosorbide; PG-propylene glycol) was chosen.

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

83.296% Propylene Glycol (PG) -EP (BASF and Inovene)

2.63% Oleic Acid (OA) -super refined oleic acid NF/EP (Croda)

1.754% Dimethylisoborbitol (DI) -Arlasolve^TM(Uniqema)

0.8% hydroxypropyl cellulose-Klucel HF grade NF/EP (Hercules)

0.02% Butylated Hydroxytoluene (BHT) -EP grade (Fluka)

11.5% meptazinol hydrochloride BP grade (Kern Pharma)

Note that the weight ratio in isolation (OA: DI: PG) was 3:2: 95.

EXAMPLE 4 transdermal Patches containing Meptazinol

Fig. 4 shows an example of a transdermal patch containing meptazinol prepared according to the present invention.

ScotchPak 9742 fluoropolymer having a thickness of 4.6 mils (mil) and a diameter of 98mm was used to form the release liner (1). A55 mm diameter D SM Solupor10PO5A with 6mm peripheral heat sealed edges was used to form microporous membrane (2). An Amcor C FILM (Amcor FlexiblesInc.) having a thickness of 6 mils (mil) and a diameter of 55mm has a 6mm peripheral heat-sealed edge (or alternatively a 54mm diameter peripheral heat-sealed edge of 5 mm) which is used to form the carrier FILM (3). Using a mixture of 2.5% Dow Corning200 fluid (tack enhancer)Dow Corning BIO PSA 7-4302 adhesive is mixed to form an adhesive ring (4), the diameter of the adhesive ring (4) is 98mm, the coating weight of the adhesive ring (4) is 85g/m, and the central hole with the diameter of 50mm²)。

The drug reservoir layer is formed by bonding a microporous film (2) and a base film (3), and has a filling capacity of 100 μ L/cm². The meptazinol composition contained in the drug reservoir was 2.5mL of the composition described in example 3.

Example 5 in vivo transdermal absorption Studies in miniature pigs

Root of Geting

Two studies were performed on minipigs involving daily administration of the patch of example 4 up to 7 days. The patch is contained in a Solupor10PO5A microporous membrane (surface area 25 cm)²) Gel reservoir above (100. mu.L/cm)²Nominal starting capacity 2.5 mL). It is fixed to the skin by a peripheral ring of adhesive film (permeter ring) and an adhesive cover. Meptazinol was given to pigs at an i.v. dose of-1 mg/kg, in individual cases, to enable determination of bioavailability.

The results of this study showed that 150-200mg of drug left the patch within a 24 hour period. The pharmacokinetic profile shows negligible lag time, with the time of maximum concentration (tmax) occurring within 8 hours. Plasma levels were maintained at steady state with a mean fluctuation index of only 2.3. Transdermal bioavailability is low, about 8% -12%, probably as a result of skin metabolism in miniature pigs. However, such an exhaustive glucuronidation reaction has not been reported for other phenolic analgesics that are applied to human skin (RoySD, Hou SY, Witham SL, Flynn GL, "Transdermal delivery of nalotic administration of drugs: synthetic methods and materials of human cadver and hair mouse skin", J Pharm Sci., Vol. 83(12) 1723-8 (1994)).

This surprising increase in skin flux rate is believed to be the result of rapid radial or lateral diffusion of the meptazinol salt upon addition of the gelling agent.

Example 6 protocol for determining the flux of live skin in humans

The following protocol was carried out to determine the transdermal flux of the meptazinol gel formulation, as well as to determine the systemic availability relative to Intravenous (IV) administration. In addition, the protocol also enables the evaluation of the safety and local tolerability of the meptazinol transdermal gel relative to the meptazinol IV (intravenous) administration and gel placebo.

Treatment A Meptazinol gel and/or patch as described in example 3 and example 4 above was applied and fixed to the inside of the forearm of 10 volunteers, blocked for 24 hours, plus simultaneous injection (slow IV injection) within 30 seconds with a single dose of intravenous placebo (sterile 0.9% w/v sodium chloride) 0.5mL injection. The meptazinol gel was administered to provide a total topical dose of 129mg of meptazinol (free base). The concentration of meptazinol hydrochloride in the gel is 100 mg/mL; 0.1mL/cm²Will cover 13cm²The surface area of the skin. This would be contained within a 4cm diameter orifice ring (stomal ring) under which the DSM10PO5A microporous membrane was placed. The ring will be closed with a surface glass.

Treatment B the corresponding gel placebo was administered and fixed to the inner side of the forearm, blocked for 24 hours, plus a simultaneous 50mg single dose of 0.5mL IV meptazinol injected over 30 seconds (slow IV injection).

All patients received two treatments for 2 dose periods. Patients are randomized for the treatment order to be selected to provide an adequate assessment of safety, tolerability, and pharmacokinetics.

This scheme is random, with the two methods crossing over in the design of the processing sequence (AB or BA). Treatment was applied on study days 1 and 4. The gel (meptazinol formulation or placebo) was applied to the skin and left for 24 hours. The administration of IV meptazinol or the corresponding IV placebo was injected as a slow pill into the arm opposite to the receiving gel. Gel was applied to the right arm on day 1 and gel was applied to the left arm on day 4.

A series of plasma and urine PK samples were collected and the skin was used to assess gel tolerance during the study hospitalization.

This protocol will evaluate the plasma concentration-time profile and pharmacokinetic parameters of meptazinol (and possible metabolites) to contain, for each patient, the C for the transdermal gel administration of meptazinol versus the intravenous administration of C_max、t_max、AUC、t_1/2And bioavailability; evaluating transdermal flux; the amount of meptazinol (and possible metabolites) excreted in urine; local tolerance, erythema and edema were assessed by visual inspection of the skin, and itching, burning or other discomfort of the individual was examined at the site of gel application supported by digital images of the site of application.

Having described in detail various specific embodiments of the present invention, it is to be understood that the invention defined by the preceding paragraphs is not to be limited to the specific details set forth above.

Claims (26)

1. A transdermal device for transdermally administering an effective amount of meptazinol to provide analgesic relief to a mammal or patient in need thereof, comprising:

(i) a bottom layer;

(ii) a reservoir or barrier;

(iii) a control film or a non-control microporous film;

(iv) an adhesive film, optionally applied as a peripheral ring or as a geometric figure or a combination thereof;

(v) a release liner; and

wherein the reservoir contains a composition; the composition comprises:

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

(b) a pharmaceutically effective carrier.

2. The transdermal device according to claim 1, wherein the device further comprises a control membrane and an adhesive and optionally a release liner.

3. The transdermal device of claim 1, wherein the device is capable of providing analgesic relief for a period selected from the group consisting of about 8 hours of analgesic relief; and about 24 hours remission to about 168 hours remission.

4. The transdermal device according to claim 1, comprising a salt of a meptazinol precursor.

5. The transdermal device according to claim 4, wherein the meptazinol precursor has formula (II):

wherein,

r forms an ester, ether or glucoside with-O-; or

Wherein R is hydrogen or absent, whereby the oxygen is negatively charged, forming a meptazinol salt.

6. The transdermal device of claim 5,

when R forms an ester, R is-C (═ O) -C₁-C₁₂-an alkyl group; -C (═ O) -C₁-C₁₂-alkyl-NR₁R₂Wherein R is₁And R₂Independently is hydrogen or C₁-C₄An alkyl group; or R is C (═ O) -C₁-C₁₂-alkyl CO₂R₃Wherein R is₃Is hydrogen, C₁-C₄Alkyl or is a cation;

when R forms an ether, R is substituted or unsubstituted C₁-C₁₂-an alkyl group, or a substituted or unsubstituted aryl group;

when R forms a glucoside, R is selected from the group consisting of monosaccharide, oligosaccharide, polysaccharide, erythrosyl, threonyl, ribosyl, arabinosyl, xylosyl, lyxosyl, allosyl, altrose, glucosyl, glucosylamino, mannosyl, gulose, idosyl, galactosyl, galactosylamino, talose, and salts thereof; another embodiment is where R is glucosyl, glucosylamino, galactosyl, galactosylamino, lactose, sucrose, trehalose, lewis a trisaccharide, 3 '-O-sulfonic acid lewis a, lewis b tetrasaccharide, lewis x trisaccharide, sialylated lewis x, 3' -O-sulfonic acid lewis x, lewis y tetrasaccharide, chitin, chitosan, cyclodextrin, dextran, pullulan; alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, dimethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and salts thereof; or wherein R is an amino acid such as C-alkyl NH₂；

When R is hydrogen but absent and oxygen is negatively charged, meptazinol salt is formed, wherein the salt form is selected from the group consisting of sodium salt, potassium salt, cesium salt, calcium salt, magnesium salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt.

7. The transdermal device according to claim 6, wherein R is hydrogen and the nitrogen in formula (II) is positively charged, the salt form is hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, maleate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, camphorsulfonate, alaninate, asparaginate, glutamate or a mixture thereof.

8. The transdermal device according to claim 7, wherein the salt form is a hydrochloride salt, a camphorsulfonate salt, a tosylate salt, a trifluoroacetate salt, a maleate salt, or a mixture thereof.

9. The transdermal device according to claim 8, wherein the meptazinol salt has a solubility selected from the group consisting of about 30mg/mL to about 500 mg/mL; about 50mg/mL to about 400mg/mL and about 75mg/mL to about 300 mg/mL.

10. The transdermal device according to claim 8, wherein said meptazinol salt has a skin flux selected from the group consisting of about 20 to about 1000 μ g/cm²H; about 50 to about 500. mu.g/cm²H; about 125 to about 250. mu.g/cm²H and from about 160 to about 200. mu.g/cm²/h。

11. The transdermal device according to claim 8, wherein the meptazinol salt is released into a skin environment having a pH selected from the group consisting of about pH2 to about pH 4.0; about pH4.0 to about pH 7.0; about pH4.0 to about pH6.0 and about pH4.0 to about pH 5.0.

12. The transdermal device according to claim 1 comprising a meptazinol salt, wherein the salt form is a hydrochloride salt, a trifluoroacetate salt or a mixture thereof having a solubility of from about 75mg/mL to about 300mg/mL and from about 75 to about 250 μ g/cm²Skin flux/h.

13. The transdermal device of claim 10, further comprising an abrasive, an absorbent, an adhesive, an anti-acne agent, an anti-caking agent, an anti-caries agent, an antidandruff agent, an antifoaming agent, an antifungal agent, an antimicrobial agent, an antioxidant, an antiperspirant, an antistatic agent, a binder, a buffering agent, a filler, a chelating agent, a colorant, a deocclusive/callosum agent/verruca remover, a preservative, a cosmetic astringent, a cosmetic biocide, a denaturant, a depilatory agent, a drug astringent, a softener, an emulsion stabilizer, a depilatory, an exfoliant, an external analgesic, a film former, a flavoring, an aroma component, a humectant, a lysing agent, an occlusion opacifier, an oxidizing agent, a pesticide, a pH adjuster, a plasticizer, a preservative, a propellant, a reducing agent, a skin whitening agent, a skin conditioning agent, a skin protectant, a slip improver, a solvent, a surfactant, a skin conditioner, Sunscreens, surface modifiers, surfactants (including detergents, emulsifiers, foam boosters, hydrotropes, solubilizers, 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.

14. The transdermal device of claim 12, further comprising an abrasive, an absorbent, an adhesive, an anti-acne agent, an anti-caking agent, an anti-caries agent, an antidandruff agent, an antifoaming agent, an antifungal agent, an antimicrobial agent, an antioxidant, an antiperspirant, an antistatic agent, a binder, a buffering agent, a filler, a chelating agent, a colorant, a deocclusive/callosum agent/verruca remover, a preservative, a cosmetic astringent, a cosmetic biocide, a denaturant, a depilatory agent, a drug astringent, a softener, an emulsion stabilizer, a depilatory, an exfoliant, an external analgesic, a film former, a flavoring, an aroma component, a humectant, a lysing agent, an occlusion opacifier, an oxidizing agent, a pesticide, a pH adjuster, a plasticizer, a preservative, a propellant, a reducing agent, a skin whitening agent, a skin conditioning agent, a skin protectant, a slip improver, a solvent, a surfactant, a skin conditioner, Sunscreens, surface modifiers, surfactants (including detergents, emulsifiers, foam boosters, hydrotropes, solubilizers, 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.

15. A method of providing an analgesic effect to a patient in need thereof comprising using the transdermal device according to claim 1.

16. The method of claim 15, wherein the analgesic effect is topical.

17. The method of claim 15, wherein the analgesic effect is systemic.

18. The method of claim 15, wherein the transdermal device is administered by iontophoresis.

19. The method of claim 15, wherein the transdermal device administration is achieved by magnetophoresis.

20. The method of claim 15, wherein the transdermal device is administered by sonophoresis.

21. The method of claim 15, wherein the transdermal administration is performed by using a lotion, cream or ointment placed in the device.

22. The method of claim 15, wherein the transdermal administration is performed by using a matrix patch in which the drug is dissolved in a suitable pressure sensitive adhesive.

23. The method of claim 15, wherein the transdermal device is administered with thermal ablation.

24. The method of claim 15, wherein the transdermal device administration is facilitated by a natural skin carrier that phosphorylates vitamin E.

25. The method of claim 15, wherein the transdermal device is administered with the use of a micro-needle.

26. A method of administering meptazinol that avoids first pass metabolism, the method consisting of transdermal administration.

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