JP2010501001A - Transdermal delivery of meptazinol - Google Patents

Abstract

Disclosed is a delivery system for delivery of meptazinol salts that increases the bioavailability of meptazinol by an effective amount that provides improved analgesia.
One embodiment of a delivery system is a transdermal device that increases the skin flow rate of meptazinol by an effective amount that provides improved analgesia. Also disclosed is a method of providing improved analgesia.
[Selection] Figure 1

Description

Related Applications and incorporation present application by literature claims priority to U.S. Provisional Application No. 60 / 822,318, filed Aug. 14, 2006. US Application No. 11 / 614,165 filed on December 21, 2006, International Application No. PCT / US2006 / 048783 filed on December 21, 2006, and US Provisional Application filed on October 19, 2006. See also 60 / 862,114 and US Provisional Application No. 60 / 753,357, filed December 21, 2005.
The above applications, and all documents cited therein or in their proceedings (“application citation documents”) and all documents cited or referenced in application citation documents, and cited herein. All documents referred to or referred to in this document ("Documents cited in this specification") and documents cited or referenced in this document are Together with the product sheet of any product mentioned in the standard and any document mentioned or contained therein, it may be included herein and used in the practice of the invention.
FIELD OF THE INVENTION This invention relates to the administration of meptazinol for analgesia, and more particularly for administering meptazinol to a patient in need thereof for an extended period at an essentially constant rate while avoiding first pass metabolism. It relates to a method and a device.

  Meptazinol is a mixed agonist-antagonist analgesic with specificity for the μ1 opioid receptor and its chemical structure is defined by the following formula (I):

The preparation of meptazinol hydrobromide is described in US Pat. No. 3,729,465, and the preparation of the free base form of meptazinol is described in US Pat. No. 4,197,241, all of which are described in these specifications. It shall be included in this specification.
Meptazinol was found to have a negligible clinical dependence due to lack of formal clinical trials and reports in the case of street use / abuse. The lack of potential addiction to meptazinol was first reported in 1987 by internationally recognized researcher Dr. Don Jasinski (Lexington, Kentucky). This property makes meptazinol all the many strong analgesics classified as “regulated pharmaceuticals” due to the prescription / preparation restrictions that accompany it, such as fentanyl (eg, Duragesik), pentazocine, oxycodone (eg, oxycontin, pecoset), And morphine.
Meptazinol also has many clinical advantages over the more commonly used opioid analgesics, including causing minimal respiratory depression, minimal sedation and no constipation Have
The minimal cause of respiratory depression makes meptazinol a preferred obstetric analgesic to avoid neonatal dyspnea. Other analgesics administered during labor, such as pethidine and diacetylmorphine, can cause considerable neonatal respiratory depression, resulting in the so-called Gray Baby Syndrome and narcotics such as naloxone to reverse this effect Often requires the use of antagonists.
Minimizing the occurrence of sedation is advantageous for treating chronic pain symptoms and helps the patient to perform a normal daily life. Sedation associated with other analgesics often induces morbid sleepiness and a dramatic decline in quality of life-patients are almost in the world to try.
The absence of constipation is an important characteristic for treating chronic pain. Constipation commonly associated with other strong analgesics can be the most painful condition, especially for older patients. For this group of patients, often the target population of strong analgesics, the lack of constipation of meptazinol is a significant advantage over other strong analgesics such as pethidine.

Furthermore, age does not appear to affect the clearance of meptazinol, which is performed by a simple single-step glucuronidation process followed by an inactive water-soluble conjugate that is filtered through the kidney. This process of conjugated metabolic clearance is not as affected by age as some other clearance mechanism, such as direct filtration of actives in the kidney, or oxidative metabolic clearance required by, for example, pethidine.
However, despite these clinical benefits, the use of meptazinol has been limited by two major disadvantages: (1) low oral bioavailability; reported average values are widespread first-pass 4-9% as a result of metabolism and (2) tendency to cause nausea and vomiting in common with other strong analgesics. Nausea and vomiting exacerbates bioavailability due to physical drug loss due to vomiting. Furthermore, since meptazinol is known to prevent gastric emptying and effectively traps some of the orally administered drug in the stomach, large amounts of meptazinol are lost by such vomiting . All of these factors lead to significantly variable plasma drug levels of meptazinol and consequent variable patient response after oral administration. Immediate improvement from moderate to severe pain is required, as patients are reluctant to continue treatment with meptazinol until the optimal dose is found for personal use. This frustration in obtaining the optimal dose level for an individual patient can lead to compliance issues and improvements in wasted medication and pain. Compliance problems are exacerbated by the need for typically 4-6 times a day as a result of frequent oral administration of meptazinol, a short plasma half-life (1.5-2.0 hours).
In recent years, transdermal delivery of strong analgesics has been found to be an effective means of overcoming many of the problems associated with oral administration. Regulating the surge in plasma drug levels normally seen after oral administration can serve to minimize vomiting associated with the relatively high C _max values resulting from rapid absorption. In the individual case of meptazinol, avoidance of vomiting is more critical to minimize the loss of drugs trapped in the stomach due to an inhibitory effect on gastric emptying.

Transdermal delivery also provides a means to avoid first-pass metabolism by the liver, which removes up to 98.1% of the oral dose in the case of meptazinol. This high first pass disappearance of the drug inevitably leads to large fluctuations between and within the plasma plasma concentration achieved. For example, in one document (Norbury HM, Franklin, RA, Graham, DF, Eur. J. Clin. Pharm., Vol. 25, pgs 77-80, (1983)), oral bioavailability is 1.89% to 18.5% Fluctuated in the range of almost 10 times.
When administered orally, meptazinol is not an inherently potent drug and requires a 200 mg dose every 4-6 hours. The average daily dose required for an effective dose is -50-100 mg close to a flow rate of ˜83-166 μg / cm ² / h from a 25 cm ² transdermal patch. Such an inherently high flow rate is an important technical challenge as it is not normally found in other transdermal products.
Examples of transdermal delivery systems in which meptazinol can generally be formulated are mentioned in the art, for example, Oshlack et al. (US Pat. No. 6,716,449—hereinafter “Oschlack”), but these systems are described as meptazinol. There is no evidence in the art that could be delivered at the required high flow rate. Oschlack refers to maintaining the predetermined concentration level or release rate of the prior art while reducing the dosage to about 1/100 to about 1/1000. That is, Oschlack does not show how the flow rate of meptazinol could be achieved by transdermal delivery.
Skin flow rate can be determined by multiplying the permeability coefficient of keptazinol (k _p / cm / h) by the water solubility of meptazinol. The water solubility of meptazinol (free base) is 0.17 mg / mL, and the permeability coefficient of meptazinol can be calculated using an empirical formula:
log k _p = -2.7 + 0.71 log P-0.0061 MW (MW of meptazinol is 233.35)
This leads to an estimated skin flow rate of meptazinol of just 5.6 μg / cm ² / h, which is approximately 1 / 15-1 / 30 of the flow rate required to achieve the analgesic effect by transdermal delivery.

Therefore, the administration of a non-toxic mixed agonist-antagonist analgesic such as meptazinol that delivers a pharmacologically effective amount of drug to achieve a sufficiently high flow rate to treat pain or provide improved analgesia. There is still a need in the art for skin delivery systems.
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.

U.S. Pat.No. 3,729,465 U.S. Pat.No. 4,197,241 U.S. Patent No. 6,716,449 U.S. Patent No. 6,818,226 U.S. Patent No. 6,791,003 U.S. Patent No. 6,787,149 U.S. Patent No. 6,716,449 U.S. Pat.No. 5,858,393 U.S. Pat.No. 5,612,382 U.S. Pat.No. 5,464,387 U.S. Pat.No. 5,023,085 U.S. Pat.No. 4,891,377 U.S. Pat.No. 4,654,209 U.S. Patent No. 6,503,190 U.S. Patent No. 6,394,094 U.S. Patent No. 5,972,372 U.S. Patent No. 5,694,947 U.S. Pat.No. 5,543,150 U.S. Pat.No. 3,920,805 US Patent Application Publication No. 2005-042292 US Patent Application Publication No. 2003-152625 US Patent Application Publication No. 2002-090390

Norbury H.M, Franklin, R.A, Graham, D.F., Eur. J. Clin. Pharm., Vol. 25, pgs 77-80, (1983) Pharmaceutical Skin Penetration Enhancement, ed. Walters et al., Marcel Dekker, Inc., (1993) Williams et al., "Penetration Enhancers", Adv. Drug Deliv. Rev., vol. 56, pgs 603-618, (2004) “Pharmaceutical Dosage Forms and Drug Delivery Systems-Chapter 10-Transdermal Drug Delivery Systems, Ointments, Creams, Lotions and Other Preparations”, ed. By Ansel et al., Williams & Wilkins, page 360, (1995) Murthy et al., "Physical and Chemical Permeation Enhancers in Transdermal Delivery of Terbutaline Sulphate", AAPS PharmSciTech. 2001; 2 (1)

Surprisingly, applicants can overcome the shortcomings in the art regarding the use of meptazinol by combining various ternary and quaternary delivery vehicles of transdermal devices, and (most unexpectedly) identifying meptazinol. It has been found that the use of this salt form provides a sufficiently high flow rate to achieve a plasma concentration effective in improving analgesia.
Accordingly, it is an object of the present invention to provide a delivery system that delivers a pharmacologically effective amount of meptazinol to avoid first-pass metabolism and to provide for pain relief or analgesia. The present invention provides a viable means of avoiding the very large first pass effects seen in meptazinol after oral administration. The present invention results in less variation in achieving plasma concentrations, improved analgesic efficacy, and better patient compliance.
Because of the sustained plasma concentration achieved with this transdermal delivery device, less frequent doses are required, further improving patient compliance.
In addition, a relatively slow increase in plasma drug concentration is expected to minimize analgesically effective plasma drug concentration fluctuations and minimize drug emetic effects that contribute to improved patient compliance.
As used herein, the terms “delivery system” and “delivery vehicle” are meant to describe a method of supplying meptazinol by transdermal transport avoiding “first pass metabolism”. First pass metabolism refers to a decrease in the bioavailability of a drug, eg, meptazinol, due to the metabolic or excretory capacity of the liver, which is a common problem associated with oral administration. Transdermal delivery differs from parenteral or injection delivery in that the latter avoids the stratum corneum, epidermis and dermis layers of the skin and delivers the active agent directly to the subcutaneous layer. As used herein, transdermal delivery is a process in which an active agent, such as meptazinol or a derivative thereof, contacts and passes through or penetrates one or more of the stratum corneum, epidermis and dermis layers of the skin. Means to describe. This passage or penetration can be achieved by:
(1) transcellular penetration (through cells);
(2) intercellular penetration (between cells); or
(3) Transattachment penetration (by follicles, sweat glands, sebaceous glands, and hair follicles).

The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts of metazinol (including those of weakly acidic phenol groups and those of weakly basic azepine nitrogen). Furthermore, it includes various other metazinol precursors derived by covalent bonding to phenolic groups such as ethers, esters and glycosides described later. Pharmaceutically acceptable salts (of phenol) include metal salts such as sodium, potassium and cesium salts; alkaline earth metals such as calcium and magnesium salts, triethylamine salts, guanidine salts and N-substituted guanidine salts Organic amine salts such as acetamidine salt, N-substituted acetamidine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc. It is not limited to. Pharmaceutically acceptable salts (of azepine) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, organic acid salts such as trifluoroacetate and maleate, sulfone Acid salts (for example, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, naphthalenesulfonate, etc., amino acids such as alanate, aspartate, glutamate, etc. Examples include, but are not limited to, salts.
Meptazinol is a chiral molecule containing a single stereocenter at the C-3 position of azepine and can therefore exist as two enantiomers (R and S stereoisomers). Reference to meptazinol for the purposes of the present invention includes each enantiomer and mixtures thereof including racemic mixtures (racemates) unless otherwise specified.
In this disclosure, and in particular in the claims and / or claims, terms such as “comprising”, “included”, “including” may have the meanings ascribed to them in US Patent Law; For example, these may mean “include”, “included”, “include”, etc., such as “consisting essentially of”, “consisting essentially of” Terms have their meanings in U.S. Patent Law, for example, these allow elements not explicitly listed and are found in the prior art or affect basic or novel features of the invention It is noted that the elements to be excluded are excluded.
These and other embodiments are disclosed or are obvious and encompassed by the following detailed description.
The following detailed description, which is given by way of example and is not intended to limit the invention only to the specific embodiments described, can be best understood with reference to the accompanying drawings.

FIG. 1 is a graph showing comparative penetration by human skin of meptazinol free base and many of its salts. FIG. 2 is a diagram showing the skin flow rate by human skin of various salts of meptazinol.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a delivery system that delivers a pharmacologically effective amount of meptazinol for pain or to provide improved analgesia. Examples of other such delivery systems include, but are not limited to, means that allow delivery of meptazinol or its salt form by parenteral injection, pulmonary absorption, topical application, sublingual administration and rectal administration. Not. Parenteral injection includes delivery by intravenous injection, subcutaneous injection, intramuscular administration, intraarterial injection, meningeal injection. Transpulmonary absorption includes the use of inhalants and aerosols. Topical administration includes administration via: (1) mucosa including but not limited to conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra and bladder mucosa; (2) skin (topical or Including transdermal delivery); (3) eyes.
In one embodiment of the invention, the delivery vehicle is for topical administration to the skin, a transdermal device that delivers a pharmacologically effective amount of meptazinol for pain or to provide analgesia improvement, a cream, Examples include but are not limited to lotions or ointments. In another embodiment of the invention, the delivery vehicle is a transdermal device.
Transdermal devices deliver a pharmacologically effective amount of meptazinol in a way that (1) controls the rate of drug delivery to the skin or (2) allows the skin to control the rate of drug absorption Is.
A transdermal device for transdermal delivery of an effective amount of meptazinol to provide improved analgesia
(a) (i) backing layer;
(ii) a reservoir layer for a salt form of meptazinol or a salt of a meptazinol precursor;
(iii) optionally a control membrane or an uncontrolled microporous membrane;
(iv) optionally an adhesive material; and
(v) optionally a device composed of a protective strip;
(b) an amount of a salt form of meptazinol or a salt of a meptazinol precursor that will deliver an effective amount of meptazinol when added to the device and when the device is applied to the skin; and
(c) Consists of a pharmaceutically effective carrier.

Backing layer, reservoir layer, control membrane, adhesive and protective release strip are described in U.S. Pat.No. 6,818,226 (skin penetration enhancer and drug delivery system including the same); U.S. Pat.No. 6,791,003 (double adhesive transdermal drug delivery system). U.S. Patent No. 6,787,149 (Topical application of opioid analgesics such as morphine); U.S. Patent No. 6,716,449 (Controlled release composition containing opioid agonist and antagonist); U.S. Patent No. 5,858,393 (transdermal formulation) U.S. Pat.No. 5,612,382 (composition for transdermal absorption of pharmaceutically active ingredients); U.S. Pat.No. 5,464,387 (transdermal delivery device); U.S. Pat. Transdermal flow enhancer); U.S. Pat.No. 4,891,377 (transdermal delivery of narcotic analgesics etorphine and analogs); U.S. Pat.No. 4,654,209 (transdermal formulation). Can be formed using conventional teachings, each of which is hereby incorporated by reference.
In other embodiments of the invention, topical delivery devices are disclosed in U.S. Patent Nos. 6,503,190; 6,394,094; 5,972,372; 5,694,947; 5,543,150; 3,920,805 and U.S. Patent Applications. It is a transvaginal ring as described in publications 2005-042292; 2003-152625 and 2002-090390. In general, the vaginal ring has a body sized to allow insertion into the vagina, for example a cylindrical shape, but other shapes can also be used and can be configured by those skilled in the art to deliver the meptazinol salts of the present invention. . Delivery of meptazinol in this way can provide pain relief by the historically reported local anesthetic activity of the drug-about 1/10 of lidocaine-or by a centrally mediated mechanism. Such an application can be found, for example, immediately after gynecological surgery.

In a preferred embodiment of the present invention, the non-controlling membrane comprises Solupor 10P05A (DSM) and adhesive tape DURO-TAK 87-608A (National Starch), and the drugs are oleic acid, dimethyl isosorbide, propylene glycol and ethanol ( Each in a certain amount of 3: 2: 70: 25).
Alternatively, the transdermal device can constitute a so-called “drug in adhesive tape” or matrix patch, the drug being a suitable pressure sensitive adhesive tape such as (but not limited to) DURO-TAK polyacrylate. Are closely distributed. The transdermal device of the present invention is an improvement over the prior art that can provide long-term relief and requires 4-6 doses per day.
In one embodiment of the invention, the transdermal device can provide analgesic relief up to about 8 hours; in other embodiments of the invention, the transdermal device provides relief from about 8 to about 24 hours. In embodiments of the invention, the transdermal device can further provide about 24 hours of relaxation to about 168 hours of relaxation.
Given the low solubility of the free base form of meptazinol free base (0.17 mg / mL aqueous solution), it is possible to derivatize meptazinol to form a precursor compound that degrades to meptazinol when it crosses one or more layers of the skin. Can be advantageous. Therefore, another embodiment of the invention is achieved by a transdermal device containing a meptazinol precursor, including but not limited to a meptazinol ester, a glycoside, a meptazinol salt, or a mixture thereof. Transdermal delivery. A meptazinol precursor is a compound that undergoes conversion in vivo to produce meptazinol (for example, cleavage of an ester bond, glycolysis, formation of a free base from a salt). The meptazinol esters, ethers and glycosides of the present invention are compounds of formula (II):

(Wherein R is an acyl group, monosaccharide, oligosaccharide or polysaccharide, or a salt of monosaccharide, oligosaccharide or polysaccharide). (In the present invention, oligosaccharide means a sugar containing 2-10 monosaccharide units covalently bonded to each other)
When R forms an ester, one embodiment of the present invention is when R is —C (═O) —C ₁ -C ₁₂ -alkyl; yet another embodiment is where R is —C ( = O) -C ₁ -C ₁₂ -alkyl-NR ₁ R _{2 where} R ₁ and R ₂ are independently hydrogen or C ₁ -C ₄ alkyl; An embodiment is when R is C (= O) -C ₁ -C ₁₂ -alkylCO ₂ R _{3 where} R ₃ is hydrogen, C ₁ -C ₄ alkyl or a cation. is there.
In an embodiment of the present invention, further, R is -C (= O) -C ₁ -C ₄ -alkyl; yet another embodiment, R is -C (= O) -C ₁ -C ₄ -Alkyl-NR ₁ R ₂ , where R ₁ and R ₂ are independently hydrogen or C ₁ -C ₄ alkyl; yet another embodiment is where R is C (= O) -C ₁ -C ₄ -alkyl CO ₂ R _{3 where} R ₃ is hydrogen, C ₁ -C ₄ alkyl or cation.
When R forms an ether, one embodiment of the present invention is when R is a substituted or unsubstituted C ₁ -C ₁₂ -alkyl or substituted or unsubstituted aryl. In other embodiments when R is an ether, R is a substituted or unsubstituted C ₁ -C ₄ -alkyl or substituted or unsubstituted phenyl. In any embodiment, the substituent is selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, and C ₁ -C ₄ -alkoxy.
When R is a monosaccharide, one embodiment of the present invention is that R is erythrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lysosyl, allosyl, altrosyl, glucosyl, glucosylamino, mannosyl, grosyl, idosyl, galactosyl, galactosylamino, Another embodiment is when R is selected from the group consisting of glucosyl, glucosylamino, galactosyl or galactosylamino and salts thereof; further embodiments of the present invention Another embodiment is when R is selected from the group consisting of glucosyl and its salts.

When R is an oligosaccharide, one embodiment of the present invention is that R is lactose, sucrose, trehalose, Lewis a trisaccharide, 3′-O-sulfonato Lewis a, Lewis b tetrasaccharide, Lewis x trisaccharide, It is selected from the group consisting of sialyl Lewis x, 3′-O-sulfonato Lewis x, Lewis y tetrasaccharide and salts thereof.
When R is a polysaccharide, one embodiment of the present invention is when R is selected from the group consisting of chitin, chitosan, cyclodextrin, dextran, and pullulan; another embodiment of the present invention is that cyclodextrin is when α-, β-, or γ-cyclodextrin; yet another embodiment of the invention, the cyclodextrin is β-cyclodextrin, dimethyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin Is the case.
Since cyclodextrins have cavities that can accommodate inclusions of compounds such as meptazinol, another embodiment of the present invention is more than adding the cyclodextrin described in R above to meptazinol and covalently binding it. Rather, it is a case where an inclusion complex can be formed.
In another embodiment of the invention, the meptazinol precursor is a salt and R is hydrogen except in the absence of it, whereby oxygen is negatively charged; one embodiment of the invention is a salt form of sodium, Potassium, cesium, calcium, magnesium, guanidine, N-substituted guanidine and acetamidine salts, N-substituted acetamidine salts, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzyl This is a case selected from the group consisting of ethylenediamine. In another embodiment of the present invention, R is hydrogen-or one of the above-mentioned substituents-and the azepine nitrogen is positively charged and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, tri Binds to fluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, alginic acid, alanic acid, aspartic acid, glutamic acid and mixtures thereof Is the case.
Surprisingly, contrary to the traditional view that lower melting points (mp) are usually associated with improved skin permeability, meptazinol azepine salts do not show such a relationship. For example, meptazinol hydrochloride (mp 184 ° C) penetrated much better than maleate (mp 102-104 ° C). The hydrochloride also showed a higher flow rate than the camsylate (mp 46-48 ° C.).

Furthermore, in contrast to conventional concepts in the art, additional unexpected results have occurred when using meptazinol salts for transdermal delivery. In general, free base is the preferred form of transdermal delivery agent due to its greater lipophilicity. For example, the skin flux of fentanyl free base is about 5 times faster than the salt form. However, in the case of meptazinol, the free base exhibits an unexpectedly poor flow rate compared to the various salt forms. For example, the flow rate of meptazinol hydrochloride is substantially greater than the free base. Previous reports in the scientific literature have shown that ion pairs, ie salts, can improve transdermal flow by beneficially enhancing the physicochemical properties of the molecule. Such strategies often use lipophilic counterions. Surprisingly, in the case of meptazinol, the use of more lipophilic counterions such as camsylate and tosylate improves flow rates than the use of stronger acid salts such as trifluoroacetic acid or hydrochloric acid. There was no effect.
In other embodiments of the invention, additional analgesics can 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 having analgesic properties such as but not limited to amitriptyline and carbamazepine.
In other embodiments of the invention, pharmaceutically effective carriers include, but are not limited to, solvents such as alcohol, isopropyl myristate, glycerol monooleate or diols such as propylene glycol. Delivery of meptazinol or a meptazinol precursor is enhanced by the use of penetration enhancers that may be included in a pharmaceutically effective carrier. In one embodiment of the present invention, suitable penetration enhancers include polyunsaturated fatty acids (PUFA) such as arachidonic acid, lauric acid, α-linolenic acid, linoleic acid, oleic acid; dimethyl isosorbide; azone; cyclopenta Decalactone; alkyl-2- (N, N-disubstituted amino) alkanoate ester (NexAct); 2- (n-nonyl) -1,3-dioxalane (SEPA); cod liver oil; derived from essential oil, saturated fatty alcohol Glycerol monoether; D-limonene; menthol and menthol ethyl ether; N-methyl-2-pyrrolidone (NMP); phospholipids; squalene; terpenes; and alcohols such as methanol, ethanol, propanol, butanol It is not limited to these. For example, Pharmaceutical Skin Penetration Enhancement, ed. Walters et al., Marcel Dekker, Inc., (1993); Williams et al., “Penetration Enhancers”, Adv. Drug Deliv. Rev. , vol. 56, pgs 603-618 , (2004).

In other embodiments of the invention, transdermal drug delivery is enhanced by iontophoresis, magnetic induction, or ultrasonic introduction. Iontophoresis involves delivering a charged compound across the skin membrane using an applied electrical field. See, for example, “Pharmaceutical Dosage Forms and Drug Delivery Systems-Chapter 10-Transdermal Drug Delivery Systems, Ointments, Creams, Lotions and Other Preparations”, ed. By Ansel et al., Williams & Wilkins, page 360, (1995). thing. Magnetic induction involves the use of a magnetic field to enhance drug delivery to the skin. See, for example, Murthy et al., “Physical and Chemical Permeation Enhancers in Transdermal Delivery of Terbutaline Sulphate”, AAPS PharmSciTech. 2001; 2 (1). Ultrasound introduction is the use of high frequency ultrasound which serves to compromise the integrity of the stratum corneum layer and improve the penetration of the compound by the skin.
Alternatively, in other embodiments of the invention, transdermal drug delivery can be performed using a variety of topical ointments, creams or lotions. Typically, these can include an oil-in-water emulsion or a water-in-oil emulsion that incorporates meptazinol or a meptazinol precursor in one suitable vehicle. 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 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 present invention, the solubility (when measured in aqueous solution) of meptazinol or a meptazinol precursor is from about 30 mg / mL to about 500 mg / mL; in yet another embodiment of the present invention, the solubility is From about 50 mg / mL to about 400 mg / mL; in yet still another embodiment of the invention, the solubility is from about 75 mg / mL to about 300 mg / mL.

In another embodiment of the invention, the skin flow rate for delivery of meptazinol or meptazinol precursor is from about 20 to about 1000 μg / cm ² / h; in yet another embodiment of the invention, meptazinol or meptazinol precursor The skin flow rate for substance delivery is from about 50 to about 500 μg / cm ² / h; yet another embodiment of the present invention is from about 75 to about 250 μg / cm ² / h. In other embodiments of the invention, the pH of the environment from which meptazinol or meptazinol precursor is released is from about pH 4.0 to about pH 7.0; in other embodiments, the pH is from about 4.0 to about 6.0; In another alternative embodiment, the pH is from about 4.0 to about 5.0.
In some cases, additional skin care ingredients may be combined with meptazinol or meptazinol precursors as a recognized effect of those techniques, including abrasives, absorbents, adhesives, anti-acne agents, anti-caking agents. , Tooth decay preventive agent, anti-dandruff agent, antifoam agent, antifungal agent, antibacterial agent, antioxidant agent, antiperspirant, antistatic agent, binder, buffering agent, bulking agent, chelating agent, coloring agent, rice bran / Octopus / wart remover, corrosion inhibitor, cosmetic astringent, cosmetic biocide, denaturant, hair remover, pharmaceutical astringent, emollient, emulsifying stabilizer, hair remover, release agent, external analgesic, paint Film-forming elements, flavoring agents, fragrance ingredients, wetting agents, cytolytic substances, occlusive agents, opacifiers, oxidizing agents, insecticides, pH adjusters, plasticizers, preservatives, propellants, reducing agents, skin-bleaching agents, Skin conditioner, skin protectant, slip conditioner, solvent, sunscreen, table Modifiers, surfactants (including detergents, emulsifiers, foam enhancers, hydrotopes, solubilizers, suspensions), suspensions (non-surfactants), UV absorbers, viscosity modifiers, viscosity reduction Agents, viscosity increasing agents (aqueous), viscosity increasing agents (non-aqueous) and mixtures thereof.
As another embodiment of the present invention, the use of the transdermal device described above can be used to provide analgesic action to a patient in need thereof to treat systemic or local pain.
Other advantages and features of the present invention will become apparent upon reading the following description given as a non-limiting example.

Example 1
Improvement of skin flow rate by using meptazinol HCl salt Analyzes the amount of drug in the receptor fluid under the skin sample at various times after application to the skin using human skin in a conventional Franz cell in vitro device Thus, transdermal penetration of meptazinol was measured. FIG. 1 shows that the meptazinol salt is surprisingly more permeable than the meptazinol free base form. Figure 2 surprisingly shows that meptazinol salts formed from stronger acids such as hydrochloride and trifluoroacetate are faster than weaker organic acids such as camsylate, tosylate or maleate. It is a figure which shows being absorbed.
The data shown in Table 1 below shows that meptazinol concentrations are sufficient to produce a long-lasting effect when the average flow rate of the various salts tested under the above test conditions is administered to patients in need thereof. It shows that it was suitable for.

NBビヒクルは、オレイン酸2%: ジメチルイソソルビド2%: プロピレングリコール96%から構成される Table 1: Variation in flow rate of meptazinol salt by human skin among subjects.

NB vehicle is composed of 2% oleic acid: 2% dimethyl isosorbide: 96% propylene glycol

  The data in Table 2 obtained using the same in vitro Franz cell technique surprisingly demonstrates that there was no correlation between lower melting point and higher solubility across skin flow rates. is there. For example, based on a conventional view in the art, meptazinol hydrochloride, which has a higher melting point than meptazinol free base, was expected to have a worse skin flow rate, but rather several times better than meptazinol free base It is. Similarly, the stronger acid salt, meptazinol hydrochloride, has a lower solubility and higher melting point than the weaker acid salt, meptazinol camsylate, tosylate or maleate. But still have unexpectedly better skin flow rates.

^* HPLCで測定した
^**視覚的評価からのみ推定した Table 2: Oleic acid 2%: Dimethylisosorbide 2%: Saturated solubility (and melting point) of meptazinol free base and selected salts in a potential delivery vehicle containing 96% propylene glycol

^* Measured by HPLC
^** Estimated only from visual assessment

  Thus, while various embodiments of the invention have been described in detail, the invention, as defined by the above paragraphs, can be subject to many obvious modifications without departing from the spirit or scope of the invention. It should be understood that the invention is not limited to the specific details set forth above.

Claims (22)

A transdermal device for transdermal delivery of an effective amount of meptazinol to provide analgesia improvement, comprising:
(a) (i) backing layer;
(ii) a reservoir layer for a salt form of meptazinol or a salt of a meptazinol precursor;
(iii) optionally a controlled membrane or a non-rate controlled microporous membrane;
(iv) optionally an adhesive material; and
(v) optionally a device composed of a protective strip;
(b) an amount of a salt of meptazinol or a salt of a meptazinol precursor that will deliver an effective amount of meptazinol when added to the device and when the device is applied to the skin; and
(c) A pharmaceutically effective carrier.   2. The transdermal device according to claim 1, wherein the device further comprises a control membrane and an adhesive material, and optionally may include a protective strip.   2. The transdermal device of claim 1, wherein the transdermal device can provide analgesic relief for a time selected from the group consisting of about 8 hours of analgesic relief; and about 24 hours of relief to about 168 hours of relief.   2. The transdermal device of claim 1, comprising a salt of a meptazinol precursor. The transdermal device of claim 4, wherein the meptazinol precursor has the formula (II):

(Wherein R forms an ester, ether or glycoside with -O-; or
R is hydrogen or absent, so that oxygen is negatively charged, a meptazinol salt). When R forms an ester, R is -C (= O) -C ₁ -C ₁₂ -alkyl; -C (= O) -C ₁ -C ₁₂ -alkyl-NR ₁ R ₂ (wherein R ₁ And R ₂ is independently hydrogen or C ₁ -C ₄ alkyl); or R is C (= O) -C ₁ -C ₁₂ -alkylCO ₂ R ₃ (wherein R ₃ Is hydrogen, C ₁ -C ₄ alkyl or is a cation);
When R forms an ether, R is a substituted or unsubstituted C ₁ -C ₁₂ -alkyl or substituted or unsubstituted aryl;
When R forms a glycoside, R is a monosaccharide, oligosaccharide, polysaccharide, erythrosyl, threosyl, ribosyl, arabinosyl, xylosyl, lysosyl, arosil, altrosyl, glucosyl, glucosylamino, mannosyl, grosyl, idosyl, galactosyl, galactosylamino, Selected from the group consisting of talosyl and salts thereof; other embodiments are such that R is glucosyl, glucosylamino, galactosyl, galactosylamino, lactose, sucrose, trehalose, Lewis a trisaccharide, 3′-O-sulfonato Lewis a Lewis b tetrasaccharide, Lewis x trisaccharide, sialyl Lewis x, 3'-O-sulfonato Lewis x, Lewis y tetrasaccharide, chitin, chitosan, cyclodextrin, dextran, pullulan; α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclo Dextrin, hydroxypropyl-β-cyclodextrin and salts thereof; or where R is an amino acid, such as -C-alkylNH ₂ ;
It is hydrogen except that R is not present, oxygen is negatively charged, and is a metazinol salt, and the salt form is sodium, potassium, cesium, calcium, magnesium, triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexyl Is selected from the group consisting of amine, N, N'-dibenzylethylenediamine,
6. A transdermal device according to claim 5.   R is hydrogen, the nitrogen of formula (II) is positively charged and the salt form is hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, maleate, tartrate, In methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate, naphthalene sulfonate, camphor sulfonate, alginate, alaninate, aspartate, glutamate or mixtures thereof The transdermal device according to claim 6, wherein   8. The transdermal device according to claim 7, wherein the salt form is hydrochloride, camphorsulfonate, toluenesulfonate, trifluoroacetate, maleate or a mixture thereof.   The meptadinol salt solubility is selected from the group consisting of about 30 mg / mL to about 500 mg / mL; about 50 mg / mL to about 400 mg / mL; and about 75 mg / mL to about 300 mg / mL. Skin device. The skin flow rate of meptazinol salt is selected from the group consisting of about 20 to about 1000 μg / cm ² / h; about 50 to about 500 μg / cm ² / h; and about 75 to about 250 μg / cm ² / h. A transdermal device according to 1.   9. The meptazinol salt is released to a skin environment having a pH selected from the group consisting of pH about 4.0 to about pH 7.0; pH about 4.0 to about pH 6.0; and pH about 4.0 to about pH 5.0. Transdermal device. Meptazinol salt having a salt form of hydrochloride, trifluoroacetate or a mixture thereof, a solubility of about 75 mg / mL to about 300 mg / mL, and a skin flow rate of about 75 to about 250 μg / cm ² / h 2. The transdermal device of claim 1, comprising:   Abrasive, absorbent, adhesive, anti-acne agent, anti-caking agent, anti-cavity agent, anti-dandruff agent, antifoam agent, antifungal agent, antibacterial agent, antioxidant, antiperspirant, antistatic agent, binding Agent, buffering agent, bulking agent, chelating agent, colorant, sea urchin / octopus / wart remover, corrosion inhibitor, cosmetic astringent, cosmetic biocide, denaturant, hair remover, pharmaceutical astringent, emollient Agent, emulsion stabilizer, hair removal agent, release agent, external analgesic agent, film-forming element, flavoring agent, fragrance component, wetting agent, cytolytic substance, occlusive agent, opacifier, oxidizing agent, insecticide, pH adjuster, Plasticizer, preservative, propellant, reducing agent, skin-bleaching agent, skin-conditioning agent, skin protection agent, slip conditioner, solvent, sunscreen, surface modifier, surfactant (detergent quality, emulsifier , Foaming enhancer, hydrotopes, solubilizer, suspending agent), suspending agent (non-surfactant), UV absorber, viscosity modifier, viscosity reducing 11. The transdermal device according to claim 10, further comprising a minor agent, a viscosity increasing agent (aqueous), a viscosity increasing agent (non-aqueous) or a mixture thereof.   Abrasive, absorbent, adhesive, anti-acne agent, anti-caking agent, anti-cavity agent, anti-dandruff agent, antifoam agent, antifungal agent, antibacterial agent, antioxidant, antiperspirant, antistatic agent, binding Agent, buffering agent, bulking agent, chelating agent, colorant, sea urchin / octopus / wart remover, corrosion inhibitor, cosmetic astringent, cosmetic biocide, denaturant, hair remover, pharmaceutical astringent, emollient Agent, emulsion stabilizer, hair removal agent, release agent, external analgesic agent, film-forming element, flavoring agent, fragrance component, wetting agent, cytolytic substance, occlusive agent, opacifier, oxidizing agent, insecticide, pH adjuster, Plasticizer, preservative, propellant, reducing agent, skin-bleaching agent, skin-conditioning agent, skin protection agent, slip conditioner, solvent, sunscreen, surface modifier, surfactant (detergent quality, emulsifier , Foaming enhancer, hydrotopes, solubilizer, suspending agent), suspending agent (non-surfactant), UV absorber, viscosity modifier, viscosity reducing 13. The transdermal device according to claim 12, further comprising a minor agent, a viscosity increasing agent (aqueous), a viscosity increasing agent (non-aqueous) or a mixture thereof.   A method of providing an analgesic effect to a patient in need thereof, comprising applying a transdermal device according to claim 1.   16. The method according to claim 15, wherein the analgesic action is local.   16. The method according to claim 15, wherein the analgesic action is systemic.   16. The method of claim 15, wherein application of the transdermal device involves iontophoresis.   16. The method of claim 15, wherein administration of the transdermal device involves magnetic induction.   16. The method of claim 15, wherein the application of the transdermal device involves ultrasound introduction.   16. The method of claim 15, wherein transdermal delivery is performed by use of a lotion, cream or ointment instead of the device.   16. The method of claim 15, wherein transdermal delivery is performed using a matrix patch in which the drug is dissolved in a suitable pressure sensitive adhesive material.

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