Methods of administering tolperisone
阅读说明：本技术 托哌酮的施用方法 (Methods of administering tolperisone ) 是由 J·卡隆 J·拉瑟 于 2018-11-19 设计创作，主要内容包括：本公开提供了用托哌酮的每日方案治疗受试者的方法,所述每日方案对肌肉痉挛或痉挛综合征有效。所述方案有效而又不损害认知功能,并且可改善认知功能,如通过各种认知和警觉性测试所测量的。(The present disclosure provides methods of treating a subject with a daily regimen of tolperisone effective for a muscle spasm or spasm syndrome. The regimen is effective without impairment of cognitive function and can improve cognitive function as measured by various cognitive and alertness tests.)
1. A method of treating a patient suffering from a muscle spasm or spasm syndrome, wherein an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat the muscle spasm or spasm syndrome without compromising cognitive function based on the patient's regular daily activities.
2. The method of claim 1, wherein one of the patient's regular daily activities is driving.
3. The method of claim 1, wherein the patient's cognitive function is determined by simulated driving testing.
4. The method of claim 3, wherein the patient has substantially the same Standard Deviation for Lateral Position (SDLP) score in the simulated driving test after tolperisone administration as the patient's SDLP score without tolperisone administration.
5. The method of claim 3, wherein the lane exceedance score in the simulated driving test after administration of tolperisone by the patient is substantially the same as the lane exceedance score of the patient without administration of tolperisone.
6. The method of claim 1, wherein cognitive function is determined by the patient's score on the Karolinska somnolence scale.
7. The method of claim 1, wherein the treatment regimen of tolperisone or a pharmaceutically acceptable salt thereof is selected to treat a muscle spasm or spasm syndrome and provide the patient with a Karolinska somnolence scale score of about 4 or less.
8. A method of treating a patient suffering from a muscle spasm or spasm syndrome, the method comprising (1) assessing the patient's routine daily activities, (2) determining whether one or more of the activities are likely to be or are being impaired by administration of a drug that is effective for treating a muscle spasm or spasm syndrome but is also known to have a sedative effect, and (3) replacing the drug with tolperisone, or a pharmaceutically acceptable salt thereof, and administering an amount of tolperisone, or a pharmaceutically acceptable salt thereof, that is effective for treating a muscle spasm or spasm syndrome without impairing the patient's routine daily activities.
9. The method of claim 8, wherein one of the patient's regular daily activities is driving.
10. The method of claim 8, wherein the amount of tolperisone, or a pharmaceutically acceptable salt thereof, administered is effective to treat a muscle spasm or spasm syndrome without impairing cognitive function in the patient.
11. The method of claim 10, wherein the patient's cognitive function is determined by simulated driving testing.
12. The method of claim 11, wherein the patient has substantially the same Standard Deviation for Lateral Position (SDLP) score in the simulated driving test after tolperisone administration as the patient's SDLP score without tolperisone administration.
13. The method of claim 11, wherein the lane exceedance score in the simulated driving test after administration of tolperisone by the patient is substantially the same as the lane exceedance score of the patient without administration of tolperisone.
14. The method of claim 10, wherein cognitive function is determined by the patient's score on the Karolinska somnolence scale.
15. The method of claim 8, wherein the amount of tolperisone, or a pharmaceutically acceptable salt thereof, administered is effective to treat a muscle spasm or spasm syndrome and provides the patient with a Karolinska somnolence scale score of about 4 or less.
16. A method of treating a patient suffering from a muscle spasm or spasm syndrome, said method comprising administering to said patient a therapeutically effective amount of tolperisone, or a pharmaceutically acceptable salt thereof, and wherein said patient was previously treated with a muscle relaxant but discontinued treatment due to the sedative effect of said muscle relaxant.
17. The method of claim 16, wherein the muscle relaxant is cyclobenzaprine hydrochloride.
18. A method of treating a patient suffering from a muscle spasm or spasm syndrome, said method comprising administering to said patient a therapeutically effective amount of tolperisone, or a pharmaceutically acceptable salt thereof, and wherein an improvement in cognitive function is also seen in said patient.
19. The method of claim 18, wherein the patient exhibits an improvement in alertness.
20. The method of claim 18, wherein the patient exhibits an improvement in the time to respond to the condition.
21. The method of claim 18, wherein the patient exhibits an improvement in the time of response during driving.
22. The method of any one of claims 1 to 21, wherein tolperisone, or a pharmaceutically acceptable salt thereof, is administered three times daily to a total daily dose of about 150mg to about 900 mg.
23. The method of claim 22, wherein tolperisone is administered in a unit dose of 50mg, 100mg, 150mg, or 200mg to a total daily dose of 150mg to 600 mg.
24. The method of any one of claims 1 to 23, wherein tolperisone is administered in the form of racemic tolperisone hydrochloride.
25. The method of any one of claims 1 to 23, wherein racemic tolperisone hydrochloride is administered to the patient and the patient receives a total daily exposure of less than 1.5 μ g of 2-methyl-1- (4-methylphenyl) -propenone (4-MMPPO).
26. The method of any one of claims 1-23, wherein tolperisone, or a pharmaceutically acceptable salt thereof, is administered to treat a patient suffering from painful muscle spasms of the back or neck.
27. The method of claim 26, wherein pain medication is also administered to the patient.
28. The method of claim 27, wherein the analgesic is a mild analgesic.
29. The method of claim 27, wherein the analgesic is an opioid, wherein the opioid is administered at a reduced dose compared to a dose required to effectively treat a patient having a painful muscle spasm in the back or neck who has not been administered tolperisone or a pharmaceutically acceptable salt thereof.
30. A method of determining the suitability of a drug for treating a patient suffering from a muscle spasm or spasm syndrome, the method comprising conducting a drive simulation study and comparing the sedative effect of the drug to a standard therapy for treating a muscle spasm or spasm syndrome.
31. The method of claim 30, wherein the standard therapy for treating a muscle spasm or spasm syndrome is treatment with cyclobenzaprine hydrochloride.
Technical Field
The present disclosure relates to methods of administering tolperisone. The present disclosure also relates to methods of treating a subject with a daily regimen of tolperisone that is effective in a muscle spasm or spasm syndrome without impairing cognitive function in the subject. The regimen may also be effective to treat a muscle spasm or spasm syndrome while improving cognitive function in the subject.
Background
Tolperisone is a central muscle relaxant that has been used for spasticity and symptomatic treatment of muscle spasms (Martindale, The Extra Pharmacopoeia, 30 th edition, page 1211). Tolperisone is also used to treat conditions including dysmenorrhea, menopausal symptoms, tetanus, and lathyrism (neurolatism).
The chemical structure of tolperisone is shown below.
As can be seen from the above structure, tolperisone contains a chiral center (as indicated by the asterisk). Chiral separation of tolperisone into its R (-) and S (+) enantiomers has been described (see, e.g., JP-A-53-40779).
Racemic tolperisone is commercially available as the hydrochloride salt and is available in forms such asAnd
Tolperisone has been shown to exhibit membrane stabilizing effects in the central and peripheral nervous systems (Ono, h., eta/., j.pharmacobio. dynam.1984,7, 171-178). Tolperisone hydrochloride is used not only to improve the different symptoms associated with spastic paralysis, but also to improve muscle tone resulting from diseases or conditions such as cervical syndrome, joint inflammation and back pain. The use of tolperisone for the treatment of neuropathic pain and pain associated with various neurological disorders is also described (see, e.g., U.S. patent application No. 2006/0004050).
Generally, central muscle relaxantsCan reduce increased muscle tone and generally has a sedative effect when used. For example, physicians prescribe skeletal muscle relaxants such as cyclobenzaprine hydrochloride (in order to
Thus, there is a need for a treatment that allows a physician to determine a daily treatment regimen for tolperisone that is most effective in treating muscle spasms or spastic syndrome without compromising cognitive function in the patient. In addition to being a highly potent non-sedative drug for the treatment of muscle spasms or spastic syndromes, the present inventors have now surprisingly found that tolperisone improves cognitive function in a test that measures alertness of a subject following administration of a drug. One useful measure of alertness described herein is the effect of a drug on a subject's ability to remain alert during driving tests.
Disclosure of Invention
In one aspect, the present disclosure provides a method of treating a patient suffering from a muscle spasm or spastic syndrome, wherein an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat the muscle spasm or spastic syndrome without compromising cognitive function based on the patient's routine daily activities.
In another aspect, the present disclosure provides a method of treating a patient suffering from a muscle spasm or spasm syndrome, the method comprising administering to the patient a therapeutically effective amount of tolperisone, or a pharmaceutically acceptable salt thereof, and wherein an improvement in the patient's cognitive function is also seen.
In another aspect, the present disclosure provides a method of treating a patient suffering from a muscle spasm or spasm syndrome, the method comprising (1) assessing the patient's routine daily activities, (2) determining whether one or more of the activities are likely to be or are being impaired by administration of a drug effective to treat a muscle spasm or spasm syndrome but also known to have a sedative effect, and (3) replacing the drug with tolperisone or a pharmaceutically acceptable salt thereof, and administering an amount of tolperisone or a pharmaceutically acceptable salt thereof effective to treat a muscle spasm or spasm syndrome without impairing the patient's routine daily activities.
In certain embodiments, the evaluation of the patient results in the physician discontinuing treatment with a sedating muscle relaxant (e.g., cyclobenzaprine) and treating the muscle spasm or spastic syndrome with tolperisone instead.
In certain embodiments, the muscle spasm or spasm syndrome is post-stroke spasticity.
In certain embodiments, the muscle spasm or spasm syndrome is one or more acute musculoskeletal disorders.
In certain other embodiments, the muscle spasm or spasm syndrome is an acute muscle spasm in the neck and/or back.
In certain other embodiments, tolperisone provides relief from neck and/or back pain resulting from an acute onset of muscle spasm.
Drawings
FIG. 1 depicts the results of a driving simulation in which the primary endpoint is the standard deviation from lateral position (SDLP). In this test, tolperisone and placebo gave equal results, confirming that tolperisone is non-sedating. However, administration of cyclobenzaprine causes a significantly impaired effect.
Figure 2 shows further data from driving simulations where the mean difference in effect of tolperisone and cyclobenzaprine versus placebo is provided.
Figure 3 shows the mean plasma concentrations of tolperisone and cyclobenzaprine after a three-day administration period.
Detailed Description
All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety for all purposes.
Definition of
It must be noted that, as used in this specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
The term "tolperisone" as well as other chemical compounds referred to herein include compounds in any pharmaceutically acceptable form thereof, including isomers (such as diastereomers and enantiomers), salts, solvates, and polymorphs, specific crystalline forms, as well as racemic mixtures and pure isomers (if applicable) of the compounds described herein.
By "pharmaceutically acceptable excipient or carrier" is meant an excipient that may optionally be included in the compositions of the present invention and that does not produce a significant adverse toxicological effect to the patient upon administration.
"pharmaceutically acceptable salts" include, but are not limited to, amino acid salts; salts prepared with inorganic acids such as chloride, sulfate, phosphate, diphosphate, bromide, and nitrate; or salts prepared from the corresponding inorganic acid forms of any of the foregoing, e.g., hydrochloride salts and the like; or salts prepared with organic acids such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, mesylate, benzoate, ascorbate, p-toluenesulfonate, palmitate, salicylate and stearate, and also etolate (estolate), glucoheptonate and lactobionate (lactobionate). Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).
"optional" or "optionally" means that the subsequently described circumstance may or may not occur, such that the description includes instances where the circumstance occurs and instances where it does not.
"substantially absent" or "substantially free of" a feature or entity means that the feature or entity is almost completely or completely absent. As used herein, tolperisone formulations that are substantially absent or substantially free of 4-MMPPO contain less than about 10ppm of 4-MMPPO.
Tolperisone compositions that have been stored under "dry conditions" are tolperisone compositions that have been stored under controlled humidity conditions (5% to 25% relative humidity) and at temperatures in the range of about 18 to 25 ℃. The tolperisone composition can be an Active Pharmaceutical Ingredient (API), or a pharmaceutical composition (powder, etc.) comprising tolperisone and one or more pharmaceutically acceptable excipients, or a finished product, such as a capsule, tablet, etc. The composition is contained in a sealed container such as a bottle, blister, pouch, or combination thereof. The composition may also be stored in the presence of a desiccant, such as silica, which is typically packaged in a package suitable for absorbing water vapor.
"anhydrous" refers to a material that is substantially free of water.
The terms "subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.
Other definitions may be found in the following sections.
Tolperisone
Tolperisone used as part of the present disclosure is commercially available or can be synthesized by a variety of methods known in the art. See, for example, U.S. patent application publication nos. 2006/0041141; ditriech et al, (1999) J.Labeledcpd.radiopharm,42: 1125-1134; japanese patent No. 0400528319920109; japanese patent No. 5403248019790309; japanese patent No. 5403627419790316; japanese patent No. 5403017819790306; japanese patent No. 5402757119790301; kazuharu et al, (1994) chem.pharm.bulletin 42(8) 1676; japanese patent No. 20,390 (1965); and hung. patent No. 144,997(1956), each of which is incorporated herein by reference in its entirety.
Such as
U.S. patent No. 9,675,598, incorporated herein by reference in its entirety for all purposes, discloses a method of detecting levels of 4-MMPPO below about 0.001% by weight (10 ppm). It is believed that the method is capable of detecting 4-MMPPO levels as low as at least 0.5 ppm.
U.S. Pat. No. 9,675,598 discloses a method of preparing tolperisone formulations substantially free of 4-MMPPO. Thus, tolperisone formulations containing less than about 10ppm of 4-MMPPO can be prepared, for example, by recrystallization and acid treatment (see examples 1 to 5 below).
Preferably, the tolperisone and tolperisone compositions described herein are stored under dry conditions. As used herein, drying conditions refer to a temperature in the range of about 18 to 23 ℃ and a relative humidity of 5% to 25%. The composition may also be stored in the presence of a desiccant, such as silica, which is typically packaged in a package suitable for absorbing water vapor.
In a preferred embodiment, the tolperisone compositions herein comprise tolperisone in the form of an acid addition salt (e.g., racemic tolperisone hydrochloride). In another preferred embodiment, the tolperisone compositions herein will also contain additional amounts of acidic additives or excipients to create a more acidic environment than that provided by tolperisone in the form of an acid addition salt. Such additives include acetic acid, succinic acid, adipic acid, propionic acid, citric acid, toluenesulfonic acid, methanesulfonic acid, and the like. Preferred acids are diacids or higher acids having more than one acidic proton (e.g., diacids, triacids, etc.). Preferably, the acid used as a stabilizer for the tolperisone composition will have a pKa of less than about 3. Preferably, the acid is anhydrous. Particularly preferred acids include citric acid and succinic acid.
Tolperisone can also be incorporated in a glassy matrix; glass formers are well known in the art and are effective in preventing chemical degradation of tolperisone, particularly degradation that leads to the formation of 4-MMPPO.
Use and treatment regimen of tolperisone
Tolperisone is a central muscle relaxant acting on the central nervous system and is mainly used to treat increased muscle tone and tone, as well as certain circulatory problems at the extremities. Tolperisone has been found to reduce experimental hypertonia and detangling, as well as inhibit reticulal reflexion facilitation without affecting cortical function. It can also improve peripheral blood flow (
Tolperisone is useful in the treatment of a number of conditions. For example, tolperisone can be administered to a subject suffering from one or more of the following disorders, including: muscle spasms, spastic syndrome, muscular soreness, myotonia, dysmenorrhea, climacteric symptoms, tetanus, lathyrism, osteoarthritis or rheumatoid arthritis (when administered in combination with a non-steroidal anti-inflammatory drug), rheumatic diseases, fibromyalgia syndrome, occupational and motor-related stresses, back pain, spasticity caused by neurological diseases, multiple sclerosis, myelopathy, encephalomyelitis, stroke, muscle hypertension, muscle contractures, myeloautomatism, occlusive vascular diseases (e.g. occlusive arteriosclerosis, diabetic angiopathy, occlusive thromboangiitis, Raynaud's disease, diffuse scleroderma), conditions caused by innervation injury (acrocyanosis, intermittent angioneurotic dyskinesia), neuropathic pain, and in individual cases venous and lymphatic circulation conditions following thrombosis, Diabetic neuropathy, postherpetic neuralgia, and leg ulcer (crural ulcer) ((R))A package insert).
Subjects to which tolperisone can be administered include children (3 months to 18 years) and adults (18 years and older).
When treating muscle spasms or spastic syndromes, the inventors have now found that based on an understanding of the subject's routine daily activities and measuring parameters related to the subject's cognitive function, an optimal daily regimen of tolperisone can be accurately calculated. For example, cognitive function may be evaluated using a functional test, such as a digital sign replacement test (DSST). Examples of measured routine daily activities include driving ability, child care ability, and routine daily functions.
The alertness level of a subject can be conveniently measured by assessing their driving performance. In one aspect, alertness of a subject can be assessed by measuring driving parameters before and after administration of tolperisone. The driving performance may be measured using road driving tests, or more conveniently using computer simulations, such as, for example, using driving scenarios on CRDDS-MiniSim (e.g., county visual-visual Attention driving scenarios; CVDA). Another measure of alertness (related to subjective degree of sleepiness) is the Karolinska Sleepiness Scale (KSS), which provides an assessment of alertness/sleepiness at a particular point in time. KSS has been found to be associated with electroencephalograms and behavioral variables.
The inventors have also surprisingly found that administration of tolperisone has a positive effect on cognitive function and, in particular, improves the alertness of a subject when tested, such as when testing driving performance and measuring reaction time. For example, according to table 8 in example 8, most of the secondary driving endpoint measures were not statistically significantly different when comparing tolperisone to placebo in a computer-simulated driving test. This confirms that unlike other muscle relaxants (such as cyclobenzaprine), tolperisone is not significantly sedating to subjects and does not cause drowsiness. However, tolperisone showed a statistically significant improvement in one of the tested parameters, i.e. response time, compared to treatment with placebo or cyclobenzaprine. Reaction time is a particularly useful measure in this test of alertness in a subject. It is expected that the response time after tolperisone administration will be better than the response time after cyclobenzaprine administration. However, it is entirely surprising that tolperisone shows superior response times compared to treatment with placebo.
Thus, in some embodiments, the present disclosure provides a method of treating a patient suffering from a muscle spasm or spasm syndrome, wherein an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat the muscle spasm or spasm syndrome without compromising cognitive function based on the patient's routine daily activities.
In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without impairment of cognitive function, characterized by no increase in Karolinska somnolence scale score compared to prior treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without impairing cognitive function, characterized by an increase in the Karolinska somnolence scale score of no more than 1 point as compared to prior treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without impairing cognitive function, characterized by an increase in the Karolinska somnolence scale score of no more than 2 points as compared to prior treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without impairing cognitive function, characterized by an increase in the Karolinska somnolence scale score of no more than 3 points as compared to prior treatment.
In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without compromising cognitive function, characterized by an increase in the Standard Deviation of Lateral Position (SDLP) in silico of less than about 10% as compared to prior to treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without compromising cognitive function, characterized by an increase in SDLP in silico of less than about 5% as compared to prior to treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat muscle spasms or spastic syndrome without compromising cognitive function, characterized by no significant increase in SDLP in silico as compared to prior treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat muscle spasms or spastic syndrome without compromising cognitive function, characterized by no significant increase in SDLP in computer simulation compared to placebo-treated patients.
In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat muscle spasms or spastic syndrome without compromising cognitive function, characterized by a lane exceedance (lane exceedance) increase in silico of less than about 10% as compared to prior to treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without compromising cognitive function, characterized by a lane exceedance increase in computer simulation of less than about 5% as compared to prior to treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat muscle spasms or spastic syndrome without compromising cognitive function, characterized by no significant increase in lane exceedance in computer simulation compared to prior treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat muscle spasms or spastic syndrome without compromising cognitive function, characterized by no significant increase in lane exceedance in computer simulation compared to placebo-treated patients.
In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without compromising cognitive function, characterized by a total impact increase in silico of less than about 10% as compared to prior to treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without compromising cognitive function, characterized by a total impact increase in silico of less than about 5% as compared to prior to treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat a muscle spasm or spastic syndrome without compromising cognitive function, characterized by no significant increase in total collisions in computer modeling as compared to prior treatment. In some embodiments, an optimal daily treatment regimen of tolperisone, or a pharmaceutically acceptable salt thereof, is selected to treat muscle spasms or spastic syndrome without compromising cognitive function, characterized by no significant increase in total collisions in computer simulation compared to placebo-treated patients.
In other embodiments, the present disclosure provides a method of treating a patient suffering from a muscle spasm or spasm syndrome, the method comprising administering to the patient a therapeutically effective amount of tolperisone, or a pharmaceutically acceptable salt thereof, and wherein an improvement in the patient's cognitive function (e.g., an improvement in alertness) is also seen.
In some embodiments, the improvement in cognitive function in the patient is characterized by an improvement in response time (i.e., time to respond to a stimulus) of at least about 20% as compared to response time measured prior to treatment with tolperisone or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in cognitive function in the patient is characterized by an improvement in response time of at least about 10% as compared to the response time measured prior to treatment with tolperisone, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in cognitive function in the patient is characterized by an improvement in response time of at least about 5% as compared to the response time measured prior to treatment with tolperisone, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in cognitive function in the patient is characterized by a significant improvement in the patient's response time when treated with tolperisone, or a pharmaceutically acceptable salt thereof, as compared to the same patient treated with placebo.
In some embodiments, the reaction time is measured using a car driving stimulus, for example, the time to begin changing the direction of the car to avoid a collision, the time to begin braking to reduce speed, and/or the time to begin moving back to the correct lane after crossing the lane. These measurements can be conveniently made during a computer simulated driving test.
Furthermore, the inventors have found that administration of tolperisone in a therapeutically effective dose in the morning after nighttime administration does not produce a hangover effect. This provides a substantial advantage in treating a subject suffering from a muscle spasm or spasm syndrome compared to a treatment regimen established with a sedating muscle relaxant (e.g., when cyclobenzaprine is administered to the subject).
In some embodiments, the patient does not experience substantial sedation after treatment with tolperisone compared to before treatment at steady state plasma concentrations. In other embodiments, the patient does not experience substantial sedation after treatment with tolperisone as compared to prior to treatment at a Tmax plasma concentration.
In some embodiments, the patient does not experience substantial sedation following treatment with tolperisone and is characterized by an absence of an increase in Karolinska somnolence scale score compared to prior treatment. In some embodiments, the patient does not experience substantial sedation following treatment with tolperisone and is characterized by an increase in the Karolinska somnolence scale score of no more than 1 point as compared to prior treatment. In some embodiments, the patient does not experience substantial sedation following treatment with tolperisone and is characterized by an increase in the Karolinska somnolence scale score of no more than 2 points compared to prior treatment. In some embodiments, the patient does not experience substantial sedation following treatment with tolperisone and is characterized by an increase in the Karolinska somnolence scale score of no more than 3 points compared to prior treatment.
In some embodiments, the present disclosure provides a method of treating a patient suffering from a muscle spasm or spasm syndrome, the method comprising (1) assessing the patient's routine daily activities, (2) determining whether one or more of the activities are likely to be or are being impaired by administration of a drug (e.g., cyclobenzaprine) that is effective for treating a muscle spasm or spasm syndrome but is also known to have a sedative effect, and (3) replacing the drug with tolperisone or a pharmaceutically acceptable salt thereof, and administering an amount of tolperisone or a pharmaceutically acceptable salt thereof that is effective for treating a muscle spasm or spasm syndrome without impairing the patient's routine daily activities.
In other embodiments, the present disclosure provides a method of treating a patient having a muscle spasm or spasm syndrome, the method comprising administering to the patient a therapeutically effective amount of tolperisone, or a pharmaceutically acceptable salt thereof, and wherein the patient was previously treated with a muscle relaxant (e.g., cyclobenzaprine), but treatment was discontinued due to the sedative effect of the muscle relaxant.
An example of a patient's routine daily activities may preferably include driving. In certain embodiments of the present disclosure, a computer-simulated driving test is used to determine the effect of muscle relaxants on driving performance.
In one embodiment, the present disclosure provides a method of treating one or more muscle disorders described herein, the method comprising administering to a patient in need thereof a therapeutically effective amount of tolperisone, or a pharmaceutically acceptable salt or hydrate thereof, wherein after the treatment, the patient does not experience a substantial change in driving performance as compared to before the treatment.
Any suitable method known to those skilled in the art may be used to measure driving performance. In certain embodiments, driving performance is measured by the standard deviation of lateral position in a computer simulation, lane exceedance in a computer simulation, or total impact in a computer simulation.
In some embodiments, the patient does not experience substantial changes in driving performance before and after treatment at steady state plasma concentrations. In other embodiments, the patient does not experience a substantial change in driving performance before and after treatment at Tmax plasma concentrations.
In some embodiments, the patient does not experience substantial changes in driving performance before and after treatment, characterized by an increase in standard deviation from lateral position (SDLP) in computer simulation of less than about 10% as compared to before the treatment. In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by an increase in SDLP in silico of less than about 5% as compared to before the treatment. In some embodiments, the patient does not experience substantial changes in driving performance before and after treatment, characterized by no significant increase in SDLP in computer simulation compared to before the treatment. In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by no significant increase in SDLP in computer simulation compared to placebo-treated patients.
In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by less than about a 10% lane overrun increase in computer simulation as compared to before the treatment. In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by less than about a 5% lane overrun increase in computer simulation as compared to before the treatment. In some embodiments, the patient does not experience substantial changes in driving performance before and after treatment, characterized by no significant increase in lane exceedance in computer simulation compared to before the treatment. In some embodiments, the patient experienced no substantial change in driving performance before and after treatment, characterized by no significant increase in lane exceedance in computer simulation compared to placebo-treated patients.
In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by a total crash increase in computer simulation of less than about 10% as compared to before the treatment. In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by a total crash increase in computer simulation of less than about 5% as compared to before the treatment. In some embodiments, the patient does not experience a substantial change in driving performance before and after treatment, characterized by no significant increase in total collisions in computer simulation compared to before the treatment. In some embodiments, the patient experienced no substantial change in driving performance before and after treatment, characterized by no significant increase in total collisions in computer simulations compared to placebo-treated patients.
In some embodiments, the treated patient does not experience a next-day residual effect (i.e., no hangover effect).
In some embodiments, one or more muscle disorders described herein is a muscle spasm or spasm syndrome. In certain other embodiments, the muscle spasm or spasm syndrome is post-stroke spasticity.
In other embodiments, the muscle spasm or spasm syndrome is one or more acute musculoskeletal disorders. In certain other embodiments, the one or more acute musculoskeletal disorders is an acute muscle spasm of the neck and/or back.
In other embodiments, tolperisone provides relief from neck and/or back pain resulting from an acute onset of muscle spasm.
In some embodiments, tolperisone is co-administered with an analgesic to treat neck and/or back pain due to muscle spasm. Suitable analgesics are well known in the art and include anti-inflammatory agents such as NSAIDs (e.g., aspirin, celecoxib, diclofenac, ibuprofen, indomethacin, tolmetin, and naproxen) and opioids (e.g., oxycodone or hydrocodone). The tolperisone and analgesic agent can be administered in a single dosage form, or preferably in separate dosage forms, administered simultaneously or separately at any convenient time interval between doses.
In some embodiments, tolperisone can exhibit additive or synergistic effects with analgesics. This may be particularly advantageous when the analgesic is an opioid and may produce an opioid-sparing effect. Thus, particular embodiments of the present disclosure provide a method of treating neck and/or back pain due to muscle spasm by administering a therapeutically effective amount of tolperisone to a subject by combination therapy with an analgesic (e.g., an opioid), wherein the analgesic (e.g., the opioid) is administered at a reduced dose compared to the dose required to effectively treat a patient suffering from back or neck painful muscle spasm (who has not yet been administered tolperisone).
The driving studies described herein (e.g., computer-simulated driving studies) are particularly useful tests that enable a regulatory body to determine whether a drug under development is suitable for development toward approval for marketing based on a combination of its effectiveness in treating muscle spasms or spastic syndrome and the sedation effect measured by the driving studies. This study is a very effective model when used with active control drugs with known sedative effects.
Accordingly, one embodiment provides a method of determining the suitability of a drug for treating a patient having a muscle spasm or spasm syndrome, the method comprising conducting a drive simulation study and comparing the sedation of the drug to a standard therapy (e.g., cyclobenzaprine) for treating the muscle spasm or spasm syndrome.
Tolperisone dosage
Generally, a therapeutically effective amount of tolperisone for an adult human will be in the range of a total daily dosage of between about 10 to about 3000 mg/day, preferably, between 25 to 2000 mg/day, more preferably, between about 50 to about 1800 mg/day. Typical dosage ranges for adults include a total daily dosage in the range of about 150 to about 1200 mg/day, preferably about 450 to about 900 mg/day to treat spasticity and about 150 to 450 mg/day to treat muscle spasms. In certain embodiments, divided doses over the course of a day are preferred, e.g., the recommended daily dose is divided into five, or four, or three, or two doses. Preferred doses include doses of about 50mg to 450mg administered three times daily. The dosage may conveniently be selected from 50 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg/day or more.
Administration can be carried out over a period of one to several days, weeks, months or longer, depending on the dosage and the exact condition to be treated. Exemplary dosing regimens will last for at least about one day, one week, about 1 to 4 weeks, 1 to 3 months, 1 to 6 months, 1 to 50 weeks, 1 to 12 months, or longer.
In some embodiments, tolperisone is administered for a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 24 weeks, or about 50 weeks.
In some embodiments, tolperisone is administered once daily, twice daily, three times daily, or four times daily, and in particular three times daily.
The dosage range for children 3 months to 18 years old is about 1 to 25 mg/kg/day, preferably about 2 to 15 mg/day, in about 2 to 4 divided doses, preferably 3 doses. Exemplary recommended dosage ranges for children include 5 to 10 mg/kg/day and 2 to 4 mg/kg/day in 2 to 3 divided doses.
In a particular embodiment of the present disclosure, tolperisone is administered three times daily (TID) in 50mg, 100mg, 150mg or 200mg unit doses to a total daily dose of 150 to 600 mg/day.
In addition, the dose of tolperisone composition administered to a subject can be limited to prevent overexposure of the subject to 4-MMPPO. Thus, in another specific embodiment, the total daily dose results in daily exposure of the patient to less than about 20 μ g, preferably less than about 10 μ g, and more preferably less than about 1.5 μ g of 4-MMPPO.
Tolperisone formulations
In addition to comprising tolperisone, the formulations of the present invention may optionally comprise one or more additional components.
In addition to tolperisone, the compositions of the present invention may also comprise one or more pharmaceutically acceptable excipients or carriers. Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), Hydrogenated Castor Oil (HCO), cremophor (polyethoxylated castor oil), carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobials, antioxidants, binders/fillers, surfactants, lubricants (e.g., calcium stearate or magnesium stearate), glidants (such as talc), disintegrants (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium), diluents, buffering agents, acids, bases, film coatings, combinations thereof, and the like.
The compositions of the present invention may comprise one or more carbohydrates such as sugars, derivatized sugars such as sugar alcohols (alditols), aldonic acids (aldonic acids), esterified sugars and/or sugar polymers. Specific carbohydrate excipients include, for example: monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, and the like; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.
Also suitable for use in the compositions of the present invention are potato-based and corn-based starches, such as sodium starch glycolate, and modified starches that are directly compressible.
Other representative excipients include inorganic salts or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and combinations thereof.
The tolperisone compositions may also include antimicrobial agents, e.g., to prevent or retard microbial growth. Non-limiting examples of antimicrobial agents suitable for use in the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimerosal (thimersol), and combinations thereof.
The compositions as provided herein may also contain one or more antioxidants. Antioxidants are used to prevent oxidation and thus deterioration of tolperisone or other components of the formulation. Antioxidants suitable for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.
Other excipients include surfactants such as polysorbates (e.g., "Tween 20" and "Tween 80"), and pluronics such as F68 and F88 (both available from BASF, Mount Olive, new jersey), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines and phosphatidylethanolamines), fatty acids and fatty esters, steroids (such as cholesterol) and chelators (such as EDTA), zinc and other such suitable cations.
Furthermore, as previously mentioned, the compositions of the present invention may optionally comprise one or more acids. Non-limiting examples of acids that can be used include those selected from the group consisting of: hydrochloric acid, acetic acid, phosphoric acid, citric acid, succinic acid, adipic acid, propionic acid, toluenesulfonic acid, methanesulfonic acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.
In a preferred embodiment, the compositions provided herein are absent an alkaline component.
The amount of any individual excipient in the composition will vary depending on the effect of the excipient, the dosage requirements of the active agent (i.e., tolperisone), and the particular needs of the composition. In general, the optimum amount of any single excipient is determined by routine experimentation, i.e., by preparing compositions containing varying amounts of excipient (from low to high), examining stability and other parameters, and then determining the range at which optimum performance is obtained without significant adverse effects.
Typically, however, the excipient will be present in the composition in an amount of from about 1% to about 99%, preferably from about 5% to about 98%, more preferably from about 15% to about 95% by weight of the excipient. Typically, the amount of excipients present in the tolperisone compositions of the present invention is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 95% by weight.
Exemplary formulations for administration include those currently on the market, e.g.,and
Tolperisone can be provided in a sustained release formulation. See, for exampleExample 9 and international patent publication No. WO 2005/094825. Controlled or sustained release formulations are generally prepared by incorporating tolperisone into carriers or vehicles (such as liposomes), nonabsorbable impermeable polymers (such as ethylene vinyl acetate copolymers and
An exemplary controlled release formulation includes a mixture of anionic and cationic polymers, such as Eudragit RS, Eudragit L, and Eudragit S. In addition, tolperisone can be encapsulated, adsorbed to, or bound to a particulate carrier. Examples of particulate carriers include those derived from polymethylmethacrylate polymers, as well as microparticles derived from poly (lactide) and poly (lactide-co-glycolide) (referred to as PLG). See, e.g., Jeffery et al, pharm. Res. (1993)10: 362-368; and McGee et al, j.microencap. (1996). The tablets or caplets may also be coated with a water-insoluble polymer, e.g.
the aforementioned Pharmaceutical Excipients are described, together with other Excipients, in "Remington: The Science & practice of Pharmacy", 19 th edition, Williams & Williams, (1995), The "Physician's Desk Reference", 52 th edition, Medical Economics, Montvale, NJ (1998) and also Kibbe, A.H., Handbook of Pharmaceutical Excipients, 3 rd edition, American Pharmaceutical Association, Washington, D.C., 2000.
Tolperisone dosage forms
Tolperisone described herein can be formulated in any form suitable for administration. Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules and pills. Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, reconstitutable powders or lyophilizates, and liquid formulations. With respect to liquid pharmaceutical compositions, solutions and suspensions are contemplated. Preferably, tolperisone is provided in a form suitable for oral administration.
For example, tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients or additives. For example, compressed tablets are prepared by compressing in a suitable tablet press the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium) and/or surfactant or dispersant.
Molded tablets are prepared, for example, by molding in a suitable tablet press a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with a coating, such as a film, sugar coating or enteric coating, to provide release in parts of the intestinal tract other than the stomach. Methods, equipment and outsourcing manufacturers for manufacturing tablets and capsules are well known in the art.
The compositions of the present invention may also be prepared in a form suitable for veterinary use.
Tolperisone administration
Methods of administering therapeutic formulations of tolperisone include, but are not limited to, oral, parenteral (including intraarterial, intraspinal, intramuscular, intraperitoneal, intravenous, subcutaneous, intramuscular, and intradermal), rectal, nasal, topical (including transdermal, aerosol, buccal, and sublingual), vaginal, intrathecal, and inhalation routes. The preferred route will vary depending on the condition and age of the recipient, the particular condition being treated, and whether tolperisone is used in combination with an analgesic, the particular combination of drugs being used.
Preferred routes of administration are intramuscular, intravenous and oral. In a particularly preferred embodiment, tolperisone is administered orally.
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