Drug combinations in parenteral dosage forms for long-term anesthesia.

Abstract

The present invention relates to a novel combination therapy for pain control and relief. More particularly, the present invention relates to a novel long-acting pharmaceutical combination in a parenteral dosage form that can be administered pre- or post-operatively without causing motor blockade. The pharmaceutical combination according to the present invention comprises ropivacaine, clonidine, betamethasone, or pharmaceutically acceptable salts and hydrates thereof.

Description

[Technical field]

[0001] The present invention relates to a novel combination therapy for controlling and relieving pain. More particularly, the present invention relates to a novel long-acting pharmaceutical combination in a parenteral dosage form that can be administered pre- or post-operatively. The pharmaceutical combination according to the present invention comprises ropivacaine, clonidine, betamethasone, or pharma- ceutical acceptable salts and hydrates thereof. [Background technology]

[0002] Local anesthetics are drugs that block the sensation of pain in the area where they are administered by reversibly blocking the sodium channels of nerve fibers, thereby inhibiting the conduction of nerve impulses. Local anesthetics exist on the market in different pharmaceutical 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 a longer action and a more comfortable state for the patient. Most local anesthetics lose their sensory effect within about 2-6 hours, which is generally not sufficient, especially in the postoperative state. Another problem with traditional local anesthetics is that their combination with other drugs is not well tolerated and causes adverse effects. Furthermore, their action is mainly dose-dependent, and higher doses are required for longer-term pain control.

[0003] US 2009 / 220611 discloses a modified release microparticle system containing an active ingredient selected from a list including several active ingredients such as anesthetics, analgesics, anticancer drugs, etc. The microparticles are said to be advantageous because they are well tolerated and can be easily and economically obtained.

[0004] Similarly, US Patent Application Publication No. 2006 / 018933 provides a modified release dosage form comprising a highly soluble active ingredient and micromatrix particles, hydrophobic release controlling agents and coatings. Again, there is a long list of alternative active ingredients including anesthetics, analgesics and steroids that can be formulated for modified release.

[0005] WO11139595 defines a particular device for administering therapeutic agents to the spine, the therapeutic agents being selected from a particular list including analgesics and anti-inflammatory agents.

[0006] WO 9851290 discloses a local anesthetic formulation for producing nerve blockade comprising an agent selected from the group consisting of a local anesthetic, a vasoconstrictor, an adrenergic drug, a vanilloid, an amphipathic solvent, a lipophilic solvent, a glucocorticoid, and a controlled or sustained release formulation.

[0007] However, these formulations of the prior art are insufficient to provide the desired comfort to the patient, especially in the postoperative state. There is no specific treatment offered as a local anesthetic that may have a longer action while being better tolerated, even if higher doses are used in the formulation. It is difficult to formulate local anesthetics with three or more active ingredients, as they may become incompatible and unacceptable. Furthermore, the combination of local anesthetics with analgesics may cause a blockade of motor neurons that may inhibit the patient's ability and movement. Local anesthetics are also not suitable for use in anesthesia for surgery involving severe tissue damage. Thus, there remains an unmet need in the state of the art to provide improved local anesthetics to enhance patient comfort. These problems are now solved by a pharmaceutical combination comprising ropivacaine, clonidine, betamethasone, or pharma- ceutically acceptable salts and hydrates thereof, as defined in the appended claims.

[0008] The pharmaceutical combination of the present invention allows for day surgery of certain operations, since patients do not need to stay overnight in hospital. It is also possible to reduce the complications of general anesthesia, since the use of general anesthesia is now eliminated. Patients do not need to take heavy analgesics and opioids, which can cause addiction. Furthermore, the novel combination of the present invention is stable and shows low toxicity due to the chemical nature and specific doses of the active ingredients used in the combination. Summary of the Invention

[0009] The present invention relates to a pharmaceutical combination in parenteral dosage form comprising the following components, or pharma-ceutically acceptable salts and hydrates thereof: [Table 1]

[0010] As mentioned above, the local anesthetic according to the present invention is ropivacaine, or its pharmaceutical salts and hydrates. More preferably, the local anesthetic is the hydrochloride salt of ropivacaine, 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.

[0011] The clonidine used in the novel combinations of the present invention is preferably clonidine hydrochloride. The dose of clonidine is preferably about 75 μg.

[0012] The corticosteroid agent according to the present invention, i.e. betamethasone or a pharma- ceutically acceptable salt thereof, has been found to be more advantageous compared to other corticosteroids such as dexamethasone and beclomethasone. The dose of betamethasone is preferably about 2 mg.

[0013] Thus, in a preferred embodiment, the combination of the invention comprises the following components: [Table 2]

[0014] In a more preferred embodiment, the combination of the present invention comprises the following components: [Table 3]

[0015] The pharmaceutical combination according to the present invention is preferably in the form of a composition as a single dose formulated in a pharma- ceutically acceptable carrier.Preferably, the pharma-ceutically acceptable carrier comprises physiological saline containing sodium and water for injection.The pharmaceutical combination may be provided in the form of a sustained release dosage form comprising a carrier selected from the group consisting of liposomes, nanocapsules and microcapsules.

[0016] The pharmaceutical combination according to the present invention is provided for use in anesthesia and pain control. Anesthesia as referred to herein may include regional anesthesia, spinal anesthesia or epidural anesthesia. The pharmaceutical combination can be administered by injection or infusion via intradermal, subcutaneous, intramuscular, intraosseous, intraperitoneal, intravenous or intravertebral route. The pharmaceutical combination provides long-lasting local anesthesia that can be used for all types of surgery. However, it is particularly useful for postoperative pain control in surgery (i.e. orthopedic surgery). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The local anesthetic combination of the present invention advantageously contains at least three different types of active ingredients, namely ropivacaine, clonidine, betamethasone, or their pharma- ceutically acceptable salts and hydrates, which have been found to be well tolerated and, surprisingly, to have a longer action in pain control without blocking motor nerves and thus causing inhibition of the patient's movements and abilities.The novel combination according to the present invention has been found to be particularly advantageous in controlling pain in orthopedic patients, more particularly in postoperative pain in orthopedic surgery.

[0018] Ropivacaine used in the present invention is a conventionally known anesthetic compound having an amide group. [ka]

[0019] Ropivacaine is preferably used as the hydrochloride salt and its S-enantiomer for acute pain management and surgical anesthesia. Intravenously administered ropivacaine has a mean half-life for the initial phase of 14 minutes, followed by a mean absorption t 1 / 2 This is followed by a slower phase in which the effective duration is about 4.2 hours (Kuthiala et al., Ropivacaine: A review of its pharmacology and clinical use, Indian J Anaesth. 2011 Mar-Apr;55(2):104-110). Thus, ropivacaine loses its sensory effect within about 4 hours, and additional doses are required for a longer effect.

[0020] Clonidine is an agent commonly used to lower blood pressure and relieve certain types of pain. Clonidine has the following general formula: [ka]

[0021] In the context of the present invention, clonidine is preferably used as its hydrochloride salt. Clonidine restricts blood flow by stimulating alpha 2 receptors and increases the duration of action of anesthesia.

[0022] Betamethasone is a corticosteroid drug known in the art having the following general formula: [ka]

[0023] The novel combination of the present invention has been particularly found to enhance patient comfort because it provides longer acting pain control that does not block motor nerves but only reduces sensation.

[0024] Thus, according to one aspect, the present invention provides a pharmaceutical combination in parenteral dosage form comprising the aforementioned active ingredients. The combination can be administered simultaneously or concomitantly for pain management in a subject. More preferably, the combination is provided as a "pharmaceutical composition" in parenteral dosage form, prepared by mixing the active ingredients in a pharmaceutically acceptable carrier. The parenteral combination of the present invention can be provided in a specific dosage form suitable for administration via intradermal, subcutaneous, intramuscular, intraosseous, intraperitoneal, intravenous or intravertebral routes. It is particularly useful in postoperative pain control in surgery, more preferably in orthopedic surgery.

[0025] In another aspect, the present invention provides a novel use of the aforementioned combination in surgical anesthesia, comprising administering said combination to a patient before, during or after a surgical procedure.The administration can be carried out, for example, via intravenous infusion or subcutaneous route, more particularly via infiltration anesthesia or epidural administration.The combination according to the present invention has been found to be particularly successful in pain management after osteotomy (bone cutting), which is generally painful for a long period of time compared to other surgical procedures.

[0026] In a further aspect, the present invention provides a novel use of the aforementioned combination in acute pain management, comprising administering said combination to a patient via the parenteral route as described above, for example by continuous infusion or intermittent injection.

[0027] In a preferred embodiment, the concentration of ropivacaine in the total volume of the injection solution ranges from 1 to 20 mg / ml, more preferably 2.5 to 5 mg / ml, and most preferably about 2.5 mg / ml. Each dose may contain 10 mg to 200 mg, more preferably about 25 mg, of local anesthetic sufficient to obtain the desired effect.

[0028] Clonidine used in the present invention may be provided in a concentration ranging from 5 to 100 μg / ml, more preferably from 5 to 10 μg / ml. Each dose may contain 2.5 μg to 100 μg, more preferably about 75 μg of clonidine. These dosage values ​​are generally lower than conventional single dosage values ​​available on the market. Thus, the present invention is advantageous in that the desired therapeutic effect can be obtained at lower dosage values, resulting in reduced adverse effects and increased tolerability of combination therapy.

[0029] Betamethasone according to the invention may be present in a concentration ranging from 0.1 to 10 mg / ml, more preferably from 0.2 to 1 mg / ml. Each dose may contain from 1 mg to 10 mg, more preferably from 1 mg to 4 mg of betamethasone. Best results are obtained with a dose of about 2 mg.

[0030] In the context of this specification, the above doses and amounts refer to the active ingredient in free base form. The pharma- ceutically acceptable salts and hydrates of said active ingredient contain the above-mentioned amounts and amounts of the active molecule equivalent to the free base form.

[0031] Preferably, the pharmaceutical combination in parenteral dosage form comprises the following components: Ropivacaine hydrochloride monohydrate, clonidine hydrochloride, Betamethasone Includes.

[0032] The pharmaceutical combination according to the present invention provides a longer and more robust effect in anesthesia for pain control, which may be desirable, particularly in severe injuries, and may be provided in the form of a sustained release dosage form comprising a carrier selected from the group consisting of liposomes, nanocapsules and microcapsules.

[0033] Further aspects and embodiments of the present invention will be apparent from the accompanying claims.

[0034] example An anesthetic formulation of ropivacaine hydrochloride monohydrate was prepared by mixing the active ingredients in saline to the following composition: The composition was administered to patients undergoing orthopedic surgery. [Table 4]

[0035] All compositions are administered by bolus injection before surgery, and patients are asked whether they feel postoperative pain at an unpleasant level at each time during the 24-hour period after surgery.It is noted that none of the patients loses mobility and cannot move their respective body parts despite anesthesia.Patients who receive the composition are able to tolerate postoperative pain without receiving additional medication within the 24-hour period, and during this period, patients feel that the pain is absent or moderate.

[0036] The composition surprisingly provided longer action in post-operative pain management without any loss of motor function, adverse effects and tolerability issues. Patients felt more comfortable without the need for intermittent dosing.

[0037] Interestingly, it has been found that the triple combination used to anesthetize patients provides a very long period of time without significant pain, loss of motor function and paresis.Without wishing to be bound by theory, the inventors believe that the central nervous system permeability to betamethasone is lower than other corticosteroids such as dexamethasone, and therefore the desired effects described above are improved with certain corticosteroids and doses of the active ingredient according to the present invention.

Claims

1. A pharmaceutical combination in parenteral dosage form comprising the following components, or pharma- ceutically acceptable salts and hydrates thereof: 【Table 1】

2. 10. The pharmaceutical combination of claim 1 in the form of a composition as a mixture in a pharma- ceutically acceptable carrier.

3. 2. The pharmaceutical combination of claim 1, wherein said combination comprises the S-enantiomer form of ropivacaine hydrochloride.

4. 4. The pharmaceutical combination of claim 3, wherein the combination comprises ropivacaine hydrochloride monohydrate.

5. 2. The pharmaceutical combination of claim 1, wherein the combination comprises clonidine hydrochloride.

6. 3. The pharmaceutical combination of claim 2, wherein the pharma- ceutically acceptable carrier comprises saline containing sodium and water for injection.

7. A pharmaceutical combination according to any one of claims 1 to 6, comprising the following ingredients: 【Table 2】

8. A pharmaceutical combination according to any one of claims 1 to 7, comprising the following ingredients: 【Table 3】

9. 2. The pharmaceutical combination of claim 1, wherein the pharmaceutical combination is in the form of a sustained release dosage form comprising a carrier selected from the group consisting of liposomes, nanocapsules and microcapsules.

10. A pharmaceutical combination in parenteral dosage form comprising the active ingredient according to claim 1 for use in anesthesia.

11. The pharmaceutical combination for use according to claim 10, wherein the anesthesia comprises regional anesthesia, spinal anesthesia or epidural anesthesia.

12. 11. The pharmaceutical combination for use according to claim 10, wherein said anesthesia comprises injection or infusion via intradermal, subcutaneous, intramuscular, intraosseous, intraperitoneal, intravenous or intravertebral routes.

13. 11. The pharmaceutical combination for use according to claim 10, wherein said use is for post-operative pain control in orthopedic surgery.

14. The pharmaceutical combination for use according to claim 13, wherein said surgery comprises an osteotomy.

15. 13. A method for preparing a pharmaceutical composition in parenteral dosage form, comprising mixing the active ingredient of claim 1 in a pharma- ceutically acceptable carrier.

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