A combination of drugs in injectable form for long-term anesthesia

Abstract

The present invention relates to a novel combination therapy for controlling and alleviating pain. In particular, the invention relates to a novel long-acting pharmaceutical composition in injectable dosage form that can be administered before or after surgery without causing motor nerve block. The pharmaceutical composition according to the present invention comprises ropivacaine, clonidine, betamethasone, or pharmaceutically acceptable salts and hydrates thereof.

Description

A combination of drugs in injectable form for long-term anesthesia Technical background The present invention relates to a novel combination therapy for controlling and alleviating pain. In particular, the invention relates to a novel long-acting pharmaceutical composition in an injectable dosage form that can be administered before or after surgery. The pharmaceutical composition according to the present invention comprises ropivacaine, clonidine, betamethasone, or pharmaceutically acceptable salts and hydrates thereof. History of the invention Local anesthetics are drugs that block pain sensation in the area where they are administered by reversibly blocking sodium channels in nerve fibers, thereby inhibiting the conduction of nerve impulses. Local anesthetics are available in various dosage forms, including solutions, creams, gels, liposomal capsules, tablets, and spray formulations. A common problem associated with local anesthetics is that their half-life is not long enough to provide longer-lasting action and greater patient comfort. Most local anesthetics lose their reasonable efficacy within about two to six hours, which is usually not sufficient, especially in the postoperative setting. Another problem with conventional local anesthetics is that they are not well tolerated when combined with other drugs and cause side effects. In addition, their action is largely dose-dependent, with higher doses required for pain management over longer periods. US 2009 / 220611 A discloses a modified release microparticle system comprising an active principle selected from a list containing several active ingredients such as anesthetics, analgesics, anticancer agents, etc. Microparticles are said to be advantageous because they are well tolerated and can be obtained easily and economically. Similarly, US 2006 / 018933 A provides a modified release dosage form comprising a highly soluble active ingredient as well as micromatrix particles, a hydrophobic release controlling agent and a coating. Again, there are long lists of alternative active ingredients including anesthetics, analgesics and steroids that can be formulated with modified release. WO 11139595 A2 defines a specific device for administering a therapeutic agent to the spine, wherein the therapeutic agent is selected from a specific list including analgesic and anti-inflammatory agents. WO 9851290 A2 discloses local anesthetic formulations for producing nerve block comprising an agent selected from the group consisting of local anesthetics, vasoconstrictors, adrenergic drugs, vanilloids, amphiphilic solvents, lipophilic solvents, extended release glucocorticoids and controlled release. However, these prior art formulations are inadequate to provide optimal patient comfort, especially in the postoperative setting. No specific treatment has been proposed as a local anesthetic that may have a longer duration of action and at the same time be more tolerable even when higher doses are used in the formulation. Formulating local anesthetics with more than two active ingredients is difficult because they may be incompatible and intolerable. Furthermore, combining local anesthetics with analgesics may cause motor neuron blockade, which may inhibit the patient's ability and movement. Local anesthetics are also not suitable for use in anesthesia of surgeries that involve severe tissue damage. Therefore, there is still an unmet need at present to provide improved local anesthetics to enhance patient comfort. These problems are now solved by a pharmaceutical composition comprising ropivacaine, clonidine, betamethasone, or pharmaceutically acceptable salts and hydrates thereof, as defined in the appended claims. With the pharmaceutical composition of the present invention, some outpatient surgeries can be performed because patients do not need to stay overnight in the hospital. Also, the side effects of general anesthesia can be reduced because its use is now eliminated. Patients do not need to take heavy painkillers and opioids that cause addiction. In addition, the new compositions of the present invention are stable and have low toxicity due to the chemical nature and specific doses of the active ingredients used in the composition. Summary of the invention The present invention relates to a pharmaceutical composition in injectable dosage form comprising the following compounds or their pharmaceutically acceptable salts and hydrates: Ingredients Amount Ropivacaine 100 to 200 mg Clonidine 2.5 to 100 micrograms Betamethasone 1 to 10 mg As noted above, the local anesthetic agent according to the present invention is ropivacaine or its pharmaceutical salts and hydrates. Preferably, the local anesthetic agent is the hydrochloride salt of ropivacaine, and more preferably ropivacaine hydrochloride monohydrate. The S-enantiomer of ropivacaine is the preferred form of the active ingredient. The dose of ropivacaine is preferably about 25 mg. Clonidine, as used in the novel compositions of the present invention, is preferably clonidine hydrochloride. The dose of clonidine is preferably about 75 micrograms. The corticosteroid agent according to the present invention, namely betamethasone or its pharmaceutically acceptable salts, is more advantageous compared to other corticosteroids such as dexamethasone and beclomethasone. The dose of betamethasone is preferably about 2 mg. Therefore, in a preferred embodiment, the composition of the present invention comprises the following materials: Composition Amount Ropivacaine 1 to 20 mg / ml Clonidine 5 to 100 µg / ml Betamethasone 0.1 to 10 mg / ml In a more preferred embodiment, the composition of the present invention comprises the following materials: Ingredients Amount Ropivacaine hydrochloride monohydrate equivalent to approximately 25 mg of ropivacaine free base Clonidine hydrochloride equivalent to approximately 75 micrograms of clonidine free base Betamethasone approximately 2 mg Saline approximately 10 mg The pharmaceutical composition according to the present invention is preferably in the form of a composition as a unit dose formulated in a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier comprises sodium-containing saline and water for injection. The pharmaceutical composition can be presented in the form of a sustained release dosage form comprising a carrier selected from the group consisting of liposomes, nanocapsules and microcapsules. The pharmaceutical composition according to the present invention is provided for use in anesthesia and pain control. Anesthesia as mentioned herein may include regional anesthesia, spinal anesthesia or epidural anesthesia. The pharmaceutical composition can be administered by injection or infusion via intradermal, subcutaneous, intramuscular, intraosseous, intraperitoneal, intravenous or intravertebral routes. The pharmaceutical composition provides long-lasting local anesthesia that can be used for a variety of surgeries. But it is particularly useful in controlling pain after surgery (i.e. orthopedic surgery). Detailed description of the invention The local anesthetic composition of the invention preferably contains at least three different types of active ingredients, namely ropivacaine, clonidine, betamethasone, or pharmaceutically acceptable salts and hydrates thereof, which are well tolerated and surprisingly have a longer effect in controlling pain without blocking the motor nerves and thus without causing motor inhibition and the patient's abilities. The novel composition according to the present invention is particularly useful in controlling pain in orthopedic patients and in particular pain after orthopedic surgery. Ropivacaine, as used in the present invention, is an anesthetic compound typically characterized by an amide group. Ropivacaine Ropivacaine is preferably used as the hydrochloride salt and its S-enantiomer for acute pain management and surgical anesthesia. Intravenous ropivacaine has a mean initial phase half-life of 14 minutes, followed by a slower phase with a mean t1 / 2 of approximately 4.2 hours (Kotyala et al., Ropivacaine: A review of its pharmacology and clinical use, Indian J Anaesth. 2011 Mar-Apr;55(2):104-110). Therefore, ropivacaine loses its reasonable efficacy within about 4 hours and additional doses are required for a longer duration of action. Clonidine is an agent commonly used to lower blood pressure and relieve certain types of pain. Clonidine has the following general formula: Clonidine In the context of the present invention, clonidine is preferably used as its hydrochloride salt. Clonidine restricts blood flow and, by stimulating α2 receptors, increases the duration of the anesthetic effect. Betamethasone is a corticosteroid agent known in this knowledge by the following general formula: Betamethasone The novel composition of the present invention particularly increases patient comfort because it provides longer-lasting pain control without blocking motor nerves, but only reducing sensation. Thus, according to one aspect, the present invention provides a pharmaceutical composition in an injectable dosage form comprising the above active ingredients. The composition can be administered simultaneously to a subject for the management of pain. Preferably, said composition is provided as a "pharmaceutical composition" in an injectable dosage form prepared by mixing said active ingredients in a pharmaceutically acceptable carrier. The injectable composition of the present invention can be provided in a specific dosage form suitable for administration via the intradermal, subcutaneous, intramuscular, intraosseous, intraperitoneal, intravenous or intravertebral routes. It is particularly useful in the control of postoperative pain in surgery, preferably in the control of postoperative pain in orthopedic surgery. In another aspect, the present invention provides a novel use of the above compound in surgical anesthesia, comprising administering said compound to a patient before, during or after surgery. For example, said administration may be by intravenous or subcutaneous infusion, and in particular by infiltration anesthesia or epidural administration. The compound according to the present invention is particularly successful for the management of pain following osteotomy (bone cutting), which is generally painful for a longer period of time compared to other surgical procedures. In another aspect, the present invention provides a novel use of the above compound in the management of acute pain comprising administering said compound to a patient via an injectable route, as mentioned above, via, for example, continuous infusion or intermittent injections. In preferred embodiments, the concentration of ropivacaine in the total volume of the injectable solution is from 1 to 20 mg / ml, preferably from 2.5 to 5 mg / ml, and preferably about 2.5 mg / ml. Each dose may contain from 10 to 200 mg, and preferably about 25 mg, of local anesthetic, which is sufficient to obtain the desired effect. Clonidine, as used in the present invention, can be provided at a concentration of from 5 to 100 micrograms / ml, preferably between 5 and 10 micrograms / ml. Each dose may contain from 2.5 micrograms to 100 micrograms, and preferably about 75 micrograms of clonidine. These dosage amounts are generally lower than typical single dose amounts available on the market. The present invention is therefore advantageous in that the desired therapeutic effect is achieved with lower dosage amounts, which in turn reduces side effects and increases the tolerability of the combination therapy. Betamethasone according to the present invention can be provided at a concentration of from 0.1 to 10 mg / ml, preferably from 0.2 to 1 mg / ml. Each dose may contain from 1 to 10 mg, preferably from 1 to 4 mg of betamethasone. The best results are obtained with a dose of about 2 mg. Within the framework of the present description, the doses and amounts mentioned above refer to the active ingredients in the free base form. Pharmaceutically acceptable salts and hydrates of the said active ingredients contain the active molecules in the above amounts and doses equivalent to the free base form. Preferably, the pharmaceutical composition in injectable dosage form comprises the following ingredients: - Ropivacaine hydrochloride monohydrate, - Clonidine hydrochloride, - Betamethasone. Although the pharmaceutical composition according to the present invention provides a longer and more potent anesthetic effect for pain control, said composition may be presented in the form of a sustained release dosage form comprising a carrier selected from the group consisting of liposomes, nanocapsules and microcapsules. This may be particularly desirable in severe injuries. Further aspects and embodiments of the present invention should be apparent from the appended claims. Example The anesthetic preparation ropivacaine hydrochloride monohydrate with the following composition was prepared by mixing the active ingredients in saline. The compositions were administered to patients undergoing orthopedic surgery. Composition Ingredients 25 mg (2.5 mg / ml) Ropivacaine hydrochloride monohydrate Clonidine hydrochloride 75 mcg (7.5 mcg / ml) Clonidine hydrochloride 2 mg (0.2 mg / ml) Betamethasone 10 ml Saline All compounds were administered preoperatively via bolus infusion, and patients were asked every hour for a 24-hour period after surgery whether they experienced any discomfort in postoperative pain. None of the patients lost their ability to move their limbs despite anesthesia. Patients who received the combination were able to tolerate postoperative pain without additional medication for a 24-hour period and reported no or moderate pain during this period. This combination surprisingly provided longer-lasting performance in managing post-operative pain without any loss of motor nerve function, adverse effects, or tolerability issues. Patients felt more comfortable without the need for intermittent doses. Interestingly, it was found that the triple combination used to anesthetize patients provides a very long period without significant pain, loss of motor function and paralysis. The inventors, without wishing to be bound by theory, believe that the central nervous system permeability for betamethasone is lower than for other corticosteroids such as dexamethasone and therefore the desired effects mentioned above are improved with the specific corticosteroid and doses of active ingredients according to the present invention.

Claims

1. A pharmaceutical composition in injectable dosage form comprising the following ingredients, or pharmaceutically acceptable salts and hydrates thereof: Compounds Amount 2. A pharmaceutical composition according to claim 1 which is in the form of a compound in admixture in a pharmaceutically acceptable carrier.

3. A pharmaceutical composition according to claim 1, wherein the composition comprises ropivacaine hydrochloride in the form of the S-enantiomer.

4. A pharmaceutical composition according to claim 3, wherein the composition comprises ropivacaine hydrochloride monohydrate.

5. A pharmaceutical composition according to claim 1, wherein the composition comprises clonidine hydrochloride.

6. A pharmaceutical composition according to claim 2, wherein said pharmaceutically acceptable carrier comprises sodium-containing saline and water for injection.

7. A pharmaceutical composition in an injectable dosage form comprising the active ingredients according to claim 1, for use in anesthesia.

8. A pharmaceutical composition for use according to claim 7, wherein the anesthesia comprises regional anesthesia, spinal anesthesia or epidural anesthesia.

9. A pharmaceutical composition for use according to claim 7 wherein the anesthesia comprises injection or infusion via intradermal, subcutaneous, intramuscular, intraosseous, intraperitoneal, intravenous or intravertebral routes.

10. A pharmaceutical composition for use according to claim 7, wherein the composition is for use in controlling postoperative pain in orthopedic surgery.

11. A pharmaceutical composition for use according to claim 10 wherein the surgery comprises an osteotomy.

12. A method of preparing a pharmaceutical composition in injectable dosage form comprising mixing the active ingredients according to claim 1 in a pharmaceutically acceptable carrier.