TW201347784A - Liquid pharmaceutical formulation containing ketorolac and tramadol - Google Patents

Abstract

The prevent invention relates to a liquid pharmaceutical composition for treating a patient having moderate to severe pain. The liquid pharmaceutical composition comprises an effective amount of ketorolac or ketorolac tromethamine, and an effective amount of tramadol or its pharmaceutically acceptable salt. The liquid pharmaceutical composition is effective in reducing pain score from 8-9 to 5.3 or less.

Description

Liquid phase pharmaceutical formulation comprising ketorolac and tramadol

This application is directed to liquid phase pharmaceutical formulations comprising ketorolac and tramadol. The present application also relates to the use of the pharmaceutical formulation for the treatment of moderate to moderately severe pain, such as post-operative pain (eg, after caesarean section or other procedures), cancer pain, visceral pain, and traumatic pain.

For physical reasons, pain can be divided into three types: injury, neurological, and mixed.

Injury pain is usually caused by noxious stimuli such as heat and incisions that directly cause damage or damage to the body or tissue. Based on the onset of pain, nociceptive pain can be further divided into two types: physical pain and visceral pain. Somatic pain results from bone, joints, muscles, skin or connective tissue that are in direct contact with external noxious stimuli. Visceral pain results from visceral compression, stretching and injury. Most people describe symptoms as pain (achy), sharp pain, tingling, and pulsation. Injury pain usually lasts for a short period of time and ends when the damage is restored. Examples of nociceptive pain include post-operative pain, sprains, fractures, burns, bumps, bruises, and inflammatory pain (in addition to inflammation caused by arthritis).

Neuropathic pain originates from spontaneous ectopic at or around the center of the nervous system Neuronal discharge. Since the etiology of insidence is usually irreversible, most neuropathic pain is chronic pain. Most people describe neuropathic pain as shooting, burning, tingling, lancinating, electric shock quality, numbness, and persistent allodynia. The nomenclature of neuropathic pain is based on the origin of the causal system of the nervous system; for example, central pain after stroke, diabetic peripheral neuropathy, post-herpetic (or post-herpetic) neuralgia, terminal cancer pain, illusion Pain in the limbs.

Mixed pain is characterized by coexisting nociceptive pain and neuropathic pain. For example, muscle pain triggers sensitization of the central or peripheral neurons, resulting in chronic low back pain, migraine, and myofascial pain.

The clinical pain intensity is rated on a scale of 0 to 10; 0 is no pain, 1-3 is mild pain, 4-6 is moderate pain and 7-10 is severe pain. For example, 8-9 is designated as moderately severe pain.

The WHO “3 Steps” guideline provides guidelines for managing pain. The "3 steps" are determined by the intensity of the pain and the analgesic activity of the drug.

(a) Step 1 mild pain: acetaminophen, NSAID or a combination of the two. Commonly used NSAIDs include aspirin, diclofenac, indomethacin, sulindac, ketoprofen, etodolac, ketorolac.

(b) Step 2 Moderate Pain: NSAID plus opiate, containing aspirin or acetaminophen with codein, oxycodon, dihydrocodeine, hydrocodon, trama Flower

(c) Step 3 Severe pain: strong opiates, including morphine, hydromorphine, methadol, levorphanol, fentanyl (fentanyl), oxycodone

It is fully recognized that acetaminophen, NSAID and opioid have their inherent defects. Acetaminophen and NSAIDs often show a ceiling effect (the upper limit of pain relief). Once this limit is reached, taking other medicines will not provide further pain relief. In addition, NSAIDs have endotoxicity in the heart, liver, gastrointestinal tract and kidneys at regular doses. Opioids often cause intolerable adverse effects such as constipation, respiratory depression, physical dependence and abuse. First, NSAIDs provide peripheral antinociceptive effects and opioids provide central antinociception.

Ketorolac (molecular weight 255.27) or ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acid derivatives, which is often used as an analgesic. Ketorolacture works by inhibiting the body's synthesis of prostaglandins. The ketorolac in oral (tablet or capsule) and intramuscular (injection) preparations of ketorolac is (S)-(-)-ketorolac (active isomer) and (R)-(+) - A racemic mixture of ketorolac. This drug is administered to treat moderate pain or to treat severe pain in combination with a reduced dose of opioid.

Tramadol (molecular weight 263.4), ie (1R, 2R)-rel-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol belongs to the class of opiate agonists. Tramadol is classified as a central nervous system drug, which is usually sold as a hydrochloride salt (tramadol hydrochloride). Tramadol hydrochloride is a weak opioid analgesic that acts on the central nervous system without anti-inflammatory activity and is used to treat moderate to severe pain. The drug has a wide range of applications, including treatment of leg restlessness syndrome and muscle fiber pain.

The present invention relates to a liquid phase pharmaceutical composition for treating a patient suffering from moderate to severe pain. The pharmaceutical composition comprises an effective amount of ketorolac or ketorolac tromethamine in an amount of the liquid formulation, and an effective amount of tramadol or a pharmaceutically acceptable salt thereof.

In one embodiment, the effective amount of ketorolac or ketorolac tromethamine is 42-52.5 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 28-35 mg.

In another embodiment, the effective amount of ketorolac or ketorolac tromethamine is 21-26.25 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 70-87.5 mg.

Figure 1 is a scatter plot of visual analog scale versus time from a first injection of a liquid phase pharmaceutical composition. K60=60mg ketorolac, K60+T40=60mg ketorolac +40mg tramadol, K45+T75=45mg ketorolac +75mg tramadol, K30+T100=30mg ketorolac +100mg tramadol, T100=100mg Quma Flower.

The present invention relates to a liquid phase pharmaceutical formulation comprising (a) ketorolac or ketorolac tromethamine (collectively referred to herein as ketorolac in the present application) and (b) tramadol or a pharmaceutically acceptable thereof The accepted salts (collectively referred to herein as tramadol) are in aqueous solution. The liquid phase ketorolac-tramadol formulation is suitable for injection, such as intravenous or intramuscular injection. The liquid phase ketorolac-tremado formulation is also suitable for oral administration. The liquid phase ketorolac-tramadol formulation is stable for at least 1 day, preferably 3 days, more preferably 7 days at room temperature (about 22-28 ° C). As used herein, "stable" means that both drugs maintain at least 80%, preferably 90% of their initial amount in solution, and the solution does not exhibit visible precipitation.

The liquid phase ketorolac-tramadol formulation provides the combined benefit of two individual drugs, ketorolac and tramadol. The advantages of the combined ketorolac-tramadol formulation include: (a) providing a short onset of pain and long duration, (b) providing a central and peripheral analgesic effect by a complementary mechanism of action, and (c) reducing each The dose of the drug, thus minimizing side effects. Also, because of the NSAID The ketorolac-tramadol formulation is superior to a single drug because of the ceiling effect, so the addition of tramadol eliminates the ceiling effect of ketorolac. Thus, the ketorolac-tromethoate formulation can be used to treat pain with moderately severe intensity. These improvements provide patients with more treatment options.

The liquid phase ketorolac-tremado solution is preferably a clear solution, but it may also be in the form of a suspension and an emulsion.

The effective dose of the liquid ketorolac-tramadol formulation is generally from about 7.5 to 60 mg of ketorolac and from 10 to 100 mg of tramadol.

The effective amount of ketorolac and tramadol may also be 42-59 mg ketorolac and 14-71 mg tramadol; preferably 42-52.5 mg ketorolac and 28-35 mg tramadol; or 45-52.5 mg ketorolac And 30-35 mg of tramadol.

The effective amount of ketorolac and tramadol may also be 9-42 mg ketorolac and 71-99 mg tramadol; preferably 18.75-26.25 mg ketorolac and 62.5-87.5 mg tramadol; or 21-26.25 mg ketone. Acid and 70-87.5 mg of tramadol.

The dose is usually formulated to 1-20 ml for intravenous injection and 0.5-2 ml for intramuscular injection. The concentration (mg/ml) of each drug in the pharmaceutical composition can be calculated by dividing the amount (mg) by the volume (ml).

The liquid phase pharmaceutical formulation contains ketorolac or ketorolac tromethamine and tramadol or a pharmaceutically acceptable salt thereof in water at a pH of from 5.0 to 8.0, preferably from pH 6 to 8. Liquid phase pharmaceutical formulations may contain saline. The liquid phase pharmaceutical formulation may also contain a buffer to stabilize the pH. The liquid phase pharmaceutical formulation may contain a pharmaceutically acceptable carrier known to those skilled in the art. For example, a known pharmaceutically acceptable carrier for injection or oral administration can be added to the liquid phase pharmaceutical formulation. In addition to ketorolac and tramadol, the liquid pharmaceutical formulation preferably does not contain any other drug or any other active ingredient. For example, the liquid pharmaceutical formulation does not contain metoclopramide (metoclopramide) or MgSO _4.

Medical use of ketorolac-tramadol formulation

The ketorolac-tramadol formulation of the present invention is suitable for managing pain to moderate to moderately severe intensity (scales 4-9 or 6-9) based on known analgesic-related mechanisms of action and reported clinical potential. To manage the pain of moderately severe intensity (scales 8-9). The ketorolac-tramadol formulation is especially useful for managing post-operative pain, cancer pain, visceral pain, and traumatic pain.

The present invention relates to a method for treating a patient suffering from moderate to moderately severe pain (pain scale 4-9, preferably 6-9, more preferably 8-9). The method comprises: identifying a patient suffering from pain, and administering to the patient an effective amount of a liquid ketorolac-tramadol formulation. As used herein, "effective amount" refers to an amount effective to reduce or alleviate pain in a patient. The present invention reduces the pain score to 5.3.

In one embodiment, the effective amount of ketorolac or ketorolac tromethamine is 42-52.5 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 28-35 mg. Preferably, the effective amount of ketorolac or ketorolac tromethamine is 45-52.5 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 30-35 mg.

In another embodiment, the effective amount of ketorolac or ketorolac tromethamine is 18.75-26.25 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 62.5-87.5 mg. Preferably, the effective amount of ketorolac or ketorolac tromethamine is 21-26.25 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 70-87.5 mg.

The liquid ketorolac/tramadol formulation can be injected intravenously or intramuscularly Or by oral injection.

Intravenous injection can be administered by bolus injection or continuous infusion; 1, 2, 3 or 4 bolus preparations are preferred. In general, the total volume of intravenous injection is 1-20 ml or 2-10 ml, and the total volume of intramuscular injection is < 2 ml, such as 0.5-1.5 ml.

The method of the invention is suitable for the treatment of moderately severe pain with a pain intensity of 8-9. The method is also suitable for treating post-operative pain, such as post-laparotomy pain, post-operative pain after surgery, severe cancer pain, visceral pain or traumatic pain.

Postoperative pain

Postoperative pain is caused by somatic and visceral pain. Somatic pain results from direct harmful pulses at the site of injury (incision). Afferent fiber sensitization at the site of injury promotes central sensitization. Visceral pain results from visceral compression, stretching and inflammation. The liquid ketorolac-tramadol formulation provides benefits to patients with pain caused by inflammation (COX1/C0X2) and visceral pain. It also enhances the anti-nociceptive response from the central nervous system by regulating the μ receptor and serotonin and norepinephrine levels.

The liquid ketorolac-tramadol formulation is particularly effective in managing post-operative pain after laparotomy for the following reasons:

(a) Visceral pain caused by uterine contractions is a major component of postoperative pain in caesarean section. Ketorolac is highly effective in reducing visceral pain.

(b) Prostaglandins are involved in tissue damage and uterine contractions. Ketorolac inhibition of PGE2 provides better anti-inflammatory and analgesic effects than acetaminophen alone.

(c) The action mechanism of the liquid ketorolac-tramadol formulation responsible for pain reduction in caesarean section includes inhibition of COX1 and COX2, sodium current, serotonin and norepinephrine reuptake, and g receptor activation.

More than half of postoperative pain patients still experience insufficient pain under current treatment Reduced. The liquid ketorolac-tramadol formulation is suitable for pain management after other types of surgery, such as coronary artery bypass grafting (CABG), lumbar disc surgery, orthopeae (orthopaedia). Tonsillectomy.

Postoperative pain is primarily acute and severe. Management of postoperative pain usually begins one hour after surgery and continues for another 48-72 hours. Since most patients live with alkane after major surgery, it is considered easy and convenient to parenterally administer analgesics. Parenteral administration of a liquid ketorolac-tramadol formulation provides benefits in increasing drug exposure and short episodes. In addition, drug absorption can vary within the first 24 hours after surgery. The preferred route of administration for post-operative pain is intravenous or intramuscular injection.

Cancer pain

Cancer pain is the result of tissue damage, chemotherapy, radiation, or surgery caused by the tumor. Cancer pain can occur at any stage of cancer. Pain intensity ranges from moderate to severe pain. Cancer patients often experience severe intolerance at the end of the period, often using highly potent opioids such as morphine.

Prostaglandin-induced inflammation and nociceptor sensitization contribute to varying degrees during the progression of cancer and nociception. Depending on the course of the cancer, cancer pain can be injurious, neurological or both. The liquid ketorolac-tramadol formulation provides benefits to patients with cancer caused by severe inflammation (prostaglandins) and abnormal excitability of the sodium channel. It also enhances the anti-nociceptive response from the central center by regulating the mu receptor and serotonin and norepinephrine levels.

The liquid ketorolac-tramadol formulation is suitable for managing cancer pain for the following reasons:

(a) Cancer pain is mainly inflammatory and neurogenic. Anti-inflammatory and nerve blocking activity The phase ketorolac-tramadol formulation effectively manages cancer pain with moderately severe intensity.

(b) The liquid ketorolac-tramadol formulation can be used in terminal cancer patients to reduce the use of morphine in pain relief.

Patients with terminal cancer who have severe pain can be acute and chronic, with occasional Moderate to severe intensity of explosive pain. To manage acute and explosive pain, IM or IV parenteral administration provides rapid and effective pain relief.

The invention is further illustrated by the following examples, which are not to be considered as limiting the scope of the invention to the specific procedures described.

Example Example 1. Compatibility experiment

a. Stability of ketorolac tromethamine

Ketolactin tromethamine (30 mg/ml, pH 6-8) was obtained from Yung Shin Pharmaceuticals. The ketorolac tromethamine solution was adjusted to different pH values (pH 5, 6, 7, 8 and 9) with HCl or NaOH and stored at room temperature. Solutions with different pH values were tested on days 0, 1, 3 and 7 to measure the amount of ketorolac tromethamine by HPLC.

The results showed that ketorolac tromethamine (30 mg/ml) was stable at room temperature for 7 days at pH 5-9; after 7 days, the ketorolac tromethamine content was 98.4-101.7%.

b. Stability of tramadol

Tramadol (50 mg/ml, pH 6-8) was obtained from Grunenthal GMBH Products. The tramadol solution was adjusted to different pH values (pH 5, 6, 7, 8 and 9) with HCl or NaOH and stored at room temperature. Solutions with different pH values were tested on days 0, 1, 3 and 7 to measure the tramadol content by HPLC.

The results showed that tramadol was stable at pH 5-8 for 7 days at room temperature; after 7 days, the tramadol content was 97.4-102.4%. At pH 9, tramadol precipitated and on day 0, 70.4% of the initial amount remained in the solution, and after days 1, 3, and 7, 56.4% of the initial amount remained in the solution.

c. Stability of ketorolac and tramadol

The ketorolac tromethamine (30 mg/ml) and tramadol (50 mg/ml) were mixed with saline to provide a keto-acid tromethamine (2 mg/ml) and tramadol (20 mg/ml). Mixture solution. The mixture solution was adjusted to different pH values (pH 5, 6, 7, 8, and 9) with HCl or NaOH and stored at room temperature. The appearance of the mixture solution was observed on days 0, 1, 3 and 7.

At pH 5.0 and 6.0, the mixture solution was clear on day 0, but with very little suspended solids, with no significant changes on days 1, 3 and 7. At pH 7.0 and 8.0, the mixture solution was clear on days 0-7. At pH 9, vigorous precipitation was observed immediately on day 0, and needle crystals were seen on days 1-7.

The results showed that the mixture solution was stable at pH 5-8 for 7 days at room temperature, but was unstable at pH 9.

Example 2. Use of ketorolac and tramadol for postoperative pain aims

The goal of this study was to test the safety profile and efficacy of premixed ketorolac and tramadol liquid formulations for postoperative pain management.

Subject

A total of 63 subjects were randomized to this study. Most subjects (>90%) underwent elective major abdominal surgery or gynaecological surgery (including laparoscopic surgery). Other subjects (<10%) underwent mastectomy.

Drug dose

Ketorolinic acid tromethamine (Keto, 30 mg/ml) was obtained from Yung Shin Pharmaceuticals Ind Co., Ltd. Tramadol hydrochloride (50 mg/ml) was obtained from Grunenthal GMBH Products. The two drugs were premixed with saline to a total volume of 12.0 ml or 12.5 ml to provide 5 different concentrations as follows.

Group 1. Only 6mg/ml ketorolac (maximum dose 60mg in 10ml), n=12

Group 2. 6mg/ml ketorolac, 4mg/ml tramadol (maximum dose of 60mg ketorolac and 40mg tramadol in 10ml), n=13

Group 3. 4.5mg/ml ketorolac, 7.5mg/ml tramadol (maximum dose of 45mg ketorolac and 75mg tramadol in 10ml), n=13

Group 4. 3 mg/ml ketorolac, 10 mg/ml tramadol (maximum dose 30 mg ketorolac and 100 mg tramadol in 10 ml), n=12

Group 5. Only 10 mg/ml tramadol (maximum dose of 100 mg tramadol in 10 ml), n=13

The initial dose of 2.5 ml (one quarter of the maximum dose) was administered to each patient by intravenous injection at time zero, followed by intravenous injection of a 2.5 ml dose every 10 minutes until the patient's pain score was <5 or The dose is exhausted.

Research plan

Subjects who rated the most severe pain scores > 5 were randomized to one of five groups of ketorolac and/or tramadol after waking up from surgery. Give the patient an initial dose of one-quarter volume (2.5 ml), and if the subject's most severe pain is still moderate to severe (pain score) 5), then 2.5 ml is given at about 10 minutes, 20 minutes and 30 minutes. Pain scores and signs of life were assessed every 5 minutes after each dose. If the subject's most severe pain score is rated <5 or the subject has received the maximum dose, the subject discontinues taking the liquid ketorolac and tramadol formulation and directs the subject to the morphine base PCA. Pump.

The visual analog scale (VAS) scoring system was used to assess the patient's pain intensity (0-10). 10 means the most severe pain and 0 means no pain. The horizontal line of 10 cm (100 mm) length is anchored by the word descriptor, and each end is "no pain" and "very severe pain". The VAS score is determined by measuring the point (mm) marked by the subject from the left hand end of the line. The study nurse measured the length from 0 (no pain) to the mark and transcribed it to a number between 0.0 cm and 10.0 cm. Pain scores at 0, 5, 10, 15, 20, 35, 30, 35, and 40 minutes were recorded for each patient.

Result analysis

All tests were based on two-sided alternative hypotheses and were achieved at a level of 5% significance.

For the efficacy endpoint, the Van Der Waerden test was performed on the cumulative total unit dose of the combined ketorolac and tramadol. (en.wikipedia.org/wiki/Van_der_Waerden_test) In addition, regression method is used to model the combination ratio (ketoacid dose: tramadol dose) and the accumulation of ketorolac and tramadol for pain relief. Correlation between total unit doses.

Fisher's exact test was used to compare the proportion of subjects with scores less than 5 in the treatment group. (en.wikipedia.org/wiki/Fisher's_exact_test)

For safety variables, an overview frequency table of adverse events is provided by the treatment group. will Descriptive statistics are used for vital signs data.

Results and summary

A plot of the mean VAS scores for each group at 0, 5, 10, 15, 20, 35, 30, 35, and 40 minutes is plotted against time from the initial injection and is shown in Figure 1.

As shown in Figure 1, patients treated with Group I (ketose-acid only), III (maximum dose of 45 mg ketorolac and 75 mg of tramadol in 10 ml) and V (tramadol) did not reduce their pain score. It drops to less than 6.

Conversely, patients treated with Group II (maximum dose of 60 mg ketorolac and 40 mg of tramadol in 10 ml) had a pain score reduced to approximately 28-35 minutes or 30-35 minutes. 5. The cumulative dose at 28-35 minutes was calculated to be 42-52.5 mg ketorolac and 28-35 mg tramadol. The cumulative dose at 30-35 minutes was calculated to be 45-52.5 mg ketorolac and 30-35 mg tramadol.

In addition, patients treated with Group IV (maximum dose of 30 mg ketorolac and 100 mg of tramadol in 10 ml) reduced the pain score to approximately 25-35 minutes or 28-35 minutes. 5.3, and the pain score is even lower at 40 minutes. When considering the adverse effects of high doses of tramadol, reach A lower dose of tramadol of the pain score of 5.3 is preferred. The cumulative dose at 25-35 minutes was calculated to be 18.75-26.25 mg ketorolac and 62.5-87.5 mg tramadol. The cumulative dose at 28-35 minutes was calculated to be 21-26.25 mg ketorolac and 70-87.5 mg tramadol.

Claims (12)

A liquid phase pharmaceutical composition for treating a patient suffering from moderate to severe pain, comprising an effective amount of ketorolac or ketorolac tromethamine and an effective amount of tramadol or an medicinal agent thereof in an aqueous formulation An acceptable salt, wherein the effective amount of ketorolac or ketorolac tromethamine is 42-52.5 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 28-35 mg. The liquid phase pharmaceutical composition of claim 1, wherein the effective amount of ketorolac or ketorolac tromethamine is 45-52.5 mg, and the tramadol or a pharmaceutically acceptable salt thereof The effective amount is 30-35 mg. A liquid phase pharmaceutical composition for treating a patient suffering from moderate to severe pain, comprising an effective amount of ketorolac or ketorolac tromethamine and an effective amount of tramadol or an medicinal agent thereof in an aqueous formulation An acceptable salt, wherein the effective amount of ketorolac or ketorolac tromethamine is 18.75-26.25 mg, and the effective amount of tramadol or a pharmaceutically acceptable salt thereof is 62.5-87.5 mg. The liquid pharmaceutical composition according to claim 3, wherein the effective amount of ketorolac or ketorolac tromethamine is 21-26.25 mg, and the tramadol or a pharmaceutically acceptable salt thereof The effective amount is 70-87.5 mg. A liquid phase pharmaceutical composition according to claim 1 or 3, wherein the patient has a pain intensity of 6-9. A liquid phase pharmaceutical composition according to claim 1 or 3, wherein the patient has a pain intensity of 8-9. A liquid phase pharmaceutical composition according to claim 6 of the patent application, which is used for causing pain in the patient The number is reduced from 8-9 to 5.3 or below. A liquid phase pharmaceutical composition according to claim 1 or 3, wherein the composition is in the form of a solution, a suspension or an emulsion. A liquid phase pharmaceutical composition according to claim 1 or 3, which has a pH of 5-8. A liquid phase pharmaceutical composition according to claim 1 or 3, wherein the pain is post-operative pain, cancer pain, visceral pain or traumatic pain. A liquid phase pharmaceutical composition according to claim 1 or 3, which is administered by intravenous injection. For example, the liquid phase pharmaceutical composition of claim 1 or 3 is administered by intramuscular injection.