HK1139870A - Improved medicinal compositions comprising buprenorphine and naloxone - Google Patents

Description

Improved pharmaceutical compositions comprising buprenorphine and naloxone

Technical Field

The present invention relates to pharmaceutical compositions containing buprenorphine and naloxone, and to the use and manufacture of said compositions as analgesics.

Background

Although opioids are particularly effective for the treatment of moderate to severe pain, their use is limited by unpleasant and potentially dangerous adverse reactions. These adverse effects may include sedation, respiratory depression, nausea, and gastrointestinal problems. Therefore, efforts have been made to reduce adverse reactions.

There are many opioids, some of which produce more pronounced adverse effects than others. Thus, careful selection of the opioid used in the analgesic composition can itself reduce the incidence and severity of adverse effects. One particularly suitable opioid is buprenorphine, which has been shown to have both agonist (morphine-like) and antagonist properties without significant physiological dependence.

Buprenorphine (the international non-proprietary Name for N-cyclopropylmethyl-7 [ α ] - [1- (S) -hydroxy-1, 2, 2-trimethyl-propyl ]6, 14-endo-ethyl bridge-6, 7, 8, 14-tetrahydronororipavine (international non-prophetary Name)) is a potent opioid partial agonist analgesic that does not have the psychomimetic effects found in other opioid analgesics. However, buprenorphine has typical side effects of opioid agonists, such as nausea and vomiting, constipation and respiratory depression in some patients, although it has limited effect on respiratory depression as a direct consequence of its partial agonist properties.

Attempts have also been made to enhance the analgesic effect of opioids by combining opioid therapy with other drugs while minimizing the incidence and severity of adverse effects.

One approach is to add a non-opioid analgesic to the opioid treatment. The rationale is that the levels of opioid required to achieve antinociception are lower and therefore the adverse effects will be reduced.

Another approach is the co-administration of an opioid agonist and a low dose opioid antagonist.

Given that effective blockade of opioid binding is associated with administration of opioid antagonists, it is generally expected that the use of such agents will not provide any improvement in pain relief, and it is also conceivable to increase pain by the partial blockade effect of the agonist in combination therewith. It has been found that in some cases antinociception may be enhanced, but human studies have led to inconsistent findings with respect to the combined use of opioid antagonists and opioid agonists, and not all studies have been successful.

One such antagonist is naloxone (international non-proprietary name for 1-N-allyl-14-hydroxynorhydromorphone) which is a narcotic antagonist.

GB2150832 describes analgesic compositions in sublingual or parenteral dosage form comprising an effective dose of buprenorphine and an amount of naloxone sufficient to cause discomfort to narcotic addicts by parenteral administration but insufficient to destroy the analgesic effect of the buprenorphine. Preferably the parenteral dosage form may comprise naloxone and buprenorphine in a weight ratio of from 1: 3 to 1: 1, and the sublingual form may comprise naloxone and buprenorphine in a weight ratio of from 1: 2 to 2: 1. The tests in GB-A-2150832 were carried out on rats.

EP 1242087A provides an analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa, the composition comprising an amount of buprenorphine which is less than the clinical dose required to achieve pain relief and an amount of naloxone such that the weight ratio of buprenorphine to naloxone is from 12.5: 1 to 27.5: 1, whereby the analgesic effect of the buprenorphine is potentiated by a low dose of naloxone. The test in EP 1242087A was carried out on rats.

Disclosure of Invention

Human studies have now been conducted and there have been new findings regarding the combined use of buprenorphine as an opioid agonist and naloxone as an opioid antagonist. These new findings expand our understanding of the therapeutic doses that can provide effective analgesia in humans.

According to a first aspect of the present invention there is provided a method of treating pain in a human patient, the method comprising transdermally or transmucosally administering buprenorphine and naloxone to said patient, wherein the weight ratio of buprenorphine to naloxone is from 2.1: 1 to 8: 1.

It is believed that in the described mode of administration, the analgesic effect of buprenorphine is potentiated by the plasma levels of naloxone achieved.

It will be understood that the terms buprenorphine and naloxone as used herein are intended to encompass simple related pharmaceutically acceptable compounds such as esters, bases and salts (e.g. acid addition salts). A particularly preferred salt is the hydrochloride salt. However, the proportions and weights referred to herein refer to the proportions and weights of buprenorphine and naloxone itself.

Application may take several minutes. Preferably, the application takes at least 1 minute, more preferably at least 2 minutes, more preferably at least 3 minutes. Administration is preferably for up to 10 minutes, more preferably for up to 7 minutes, more preferably for up to 5 minutes.

Suitably, the method comprises transdermal or transmucosal administration of buprenorphine and naloxone to a human patient in a buprenorphine to naloxone weight ratio of 2.2: 1 or 2.3: 1 or 2.4: 1 or 2.5: 1 or 3: 1 or 3.5: 1.

Preferably, the method employs transdermal or transmucosal administration of buprenorphine and naloxone to a human patient in a weight ratio of at most 7.5: 1 or at most 6.8: 1 or at most 6.4: 1 or at most 6: 1 or at most 5.5: 1 or at most 4.5: 1. A particularly preferred weight ratio of buprenorphine to naloxone is 4: 1.

The unit dosage form for transdermal or transmucosal administration may be, for example, a tablet, film, spray, patch, rub-in composition, or lozenge. Administration, which will be further detailed in the second aspect, may comprise delivery of a medicament comprising buprenorphine and naloxone, preferably in such form.

Transdermal administration may encompass any mode of administration through the dermis. Transmucosal administration can encompass any mode of administration through the mucosa, including, for example, vaginal and rectal mucosa, preferably oral-nasal mucosa, e.g., nasal, laryngeal, oral, sublingual sites. Nasal and sublingual administration are particularly preferred.

It is preferred that the compositions for use in the methods are formulated in unit dosage forms, i.e. physically discrete units comprising suitable amounts of buprenorphine and naloxone, together with pharmaceutically acceptable diluents and/or carriers; such unit dosage forms are in a form suitable for transdermal or transmucosal administration.

Compositions in the form of lozenges and tablets for use in the method suitably comprise soluble excipients selected from substances such as lactose, mannitol, dextrose, sucrose or mixtures thereof. They also suitably comprise a granulating and disintegrating agent selected from materials such as starch, binders such as povidone or hydroxypropylmethylcellulose and lubricants such as magnesium stearate.

The compositions of the invention may comprise a buffer system, for example organic acids and salts thereof, such as citric acid and sodium citrate.

Compositions suitable for transdermal or transmucosal administration as described above may be prepared by manufacturing techniques well known to those skilled in the art.

According to a second aspect of the present invention there is provided the use of buprenorphine and naloxone in the manufacture of a medicament for the treatment of pain in a human patient, wherein the medicament is for transdermal or transmucosal administration and the buprenorphine and naloxone are provided in the medicament in a buprenorphine to naloxone weight ratio of from 2.1: 1 to 8: 1.

The use of buprenorphine and naloxone in the manufacture of a medicament according to the second aspect may comprise any of the features as described for the first aspect.

Thus, the preferred ratio of buprenorphine to naloxone in the medicament is preferably as defined above for the first aspect.

In humans, as described in EP 1242087B, in the absence of potentiation, a suitable dose of buprenorphine of about 40 μ g per kilogram of body weight is required to obtain satisfactory pain relief. Thus, for a typical body weight of 50kg to 80kg, the dose of buprenorphine will be 2mg to 3.2mg buprenorphine per day. This may conveniently be administered in four unit doses.

The amount of buprenorphine required to be effective in the compositions of the invention is less than that required to be effective in the absence of the potentiating effect of naloxone.

Importantly, when equal doses of buprenorphine with and without the potentiating effect of naloxone were compared, it was found that the degree and duration of analgesia achieved by the former composition (i.e., also containing naloxone) was significantly increased. Thus, when combined with naloxone, the same analgesic effect can be achieved with a lower dose of buprenorphine. It may therefore be proposed that, within the therapeutic range or over the entire therapeutic range, an increase in the analgesic effect can be achieved and/or that a reduced concentration of buprenorphine can be used.

Suitably, a unit dose of a composition of the invention comprising naloxone comprises buprenorphine in an amount which is lower than the amount in a unit dose of buprenorphine without naloxone required to obtain corresponding pain relief.

Suitably, at least 10 μ g, preferably at least 15 μ g, more preferably at least 20 μ g, more preferably at least 30 μ g, most preferably at least 40 μ g of buprenorphine per unit dose is included in the compositions of the invention. These values reflect the benefits of the present invention to achieve analgesia at low doses.

Suitably, the compositions of the present invention may comprise buprenorphine in any amount up to the upper limit of conventional clinical practice. Suitably, the composition may comprise at most 32mg, preferably at most 16mg, more preferably at most 8mg, more preferably at most 4mg, more preferably at most 2mg, more preferably at most 1mg, more preferably at most 600 μ g, more preferably at most 400 μ g, more preferably at most 200 μ g, more preferably at most 160 μ g, more preferably at most 100 μ g of buprenorphine per unit dose.

Suitably, according to the invention, at least 0.25 μ g/kg (body weight) of buprenorphine is administered to the patient every 24 hours. Preferably, the amount is at least 0.5. mu.g/kg, more preferably at least 1. mu.g/kg, more preferably at least 1.5. mu.g/kg, and most preferably at least 2. mu.g/kg.

Suitably, in accordance with the invention, at most 640 mug/kg of buprenorphine is administered to the patient every 24 hours. The amount is preferably at most 320. mu.g/kg, more preferably at most 160. mu.g/kg, more preferably at most 80. mu.g/kg, more preferably at most 40. mu.g/kg, more preferably at most 20. mu.g/kg, more preferably at most 16. mu.g/kg, more preferably at most 12. mu.g/kg. Most preferably the amount is at most 8. mu.g/kg.

Suitably, the amount of buprenorphine administered to the patient for the purpose of achieving pain relief by use of the composition of the invention is at least 40 μ g, preferably at least 60 μ g, more preferably at least 80 μ g, more preferably at least 120 μ g, most preferably at least 160 μ g per 24 hours.

Suitably, the amount of buprenorphine administered to the patient for the purpose of achieving pain relief by administration of a composition of the invention is at most 32mg, preferably at most 16mg, more preferably at most 8mg, more preferably at most 4mg, more preferably at most 2mg, more preferably at most 1mg, more preferably at most 800 μ g, more preferably at most 600 μ g, more preferably at most 400 μ g, more preferably at most 200 μ g, more preferably at most 160 μ g, more preferably at most 100 μ g.

Suitably, the composition comprises naloxone in an amount of at least 1 μ g per unit dose, preferably at least 1.5 μ g per unit dose, more preferably at least 2 μ g per unit dose, most preferably at least 4 μ g per unit dose.

Suitably, the composition comprises naloxone in an amount of at most 4mg per unit dose, preferably at most 2mg per unit dose, more preferably at most 1mg per unit dose, more preferably at most 500 μ g per unit dose, more preferably at most 300 μ g per unit dose, more preferably at most 200 μ g per unit dose, more preferably at most 100 μ g per unit dose, more preferably at most 80 μ g per unit dose, most preferably at most 50 μ g per unit dose.

Suitably, the amount of naloxone administered is at least 0.025 μ g naloxone/kg per 24 hours. Preferably, the amount is at least 0.05. mu.g/kg, more preferably at least 0.1. mu.g/kg, more preferably at least 0.15. mu.g/kg, more preferably at least 0.2. mu.g/kg, and most preferably at least 0.4. mu.g/kg.

Suitably, the amount of naloxone administered is at most 320 μ g naloxone/kg body weight per 24 hours. Preferably the amount is at most 160 μ g/kg body weight, more preferably at most 80 μ g/kg body weight, more preferably at most 40 μ g/kg body weight, more preferably at most 20 μ g/kg body weight, more preferably at most 10 μ g/kg body weight, more preferably at most 8 μ g/kg body weight, more preferably at most 6 μ g/kg body weight. Preferably the amount is at most 4 mug/kg body weight per 24 hours.

Suitably, the amount of naloxone administered is at least 5 μ g, more preferably at least 8 μ g, more preferably at least 10 μ g, more preferably at least 15 μ g, most preferably at least 20 μ g per 24 hours.

Suitably, the amount of naloxone administered is at most 16mg, preferably at most 8mg, more preferably at most 4mg, more preferably at most 2mg, more preferably at most 1mg, more preferably at most 500 μ g, more preferably at most 400 μ g, more preferably at most 300 μ g, most preferably at most 200 μ g per 24 hours.

The above reference values for the amount of compound that can be administered to a patient are reference values for an adult patient.

Whatever the absolute amounts of buprenorphine and naloxone administered, the definitions described herein regarding the ratio of buprenorphine to naloxone must be met.

According to a third aspect of the present invention there is provided a composition for use in the treatment of pain in a human patient, wherein the composition comprises buprenorphine and naloxone in a weight ratio of from 2.1: 1 to 8: 1, the amounts of buprenorphine and naloxone being suitable to provide analgesia, the composition being in a transdermal or transmucosal dosage form.

Suitably, the composition comprises an agent as described in the second aspect.

The use of the composition may comprise use in a method according to the first aspect.

The composition of the third aspect may comprise any of the features described for the first and/or second aspects.

The invention will now be illustrated by way of example with reference to the following examples.

Medicament

All materials except magnesium stearate were sieved through a 750 μm sieve and mixed together to prepare sublingual tablets having the following composition:

then, the mixed powder was subjected to an aqueous granulation process and dried at 50 ℃. The granules obtained were forced through a 750 μm sieve and mixed with magnesium stearate (magnesium stearate pre-sieved through a 500 μm sieve). The tablet granules were compressed to produce tablets having a diameter of 5.56mm and a weight of 60 mg.

Nociceptive testing

The cold Compression (CP) test was used to evaluate the antinociception of buprenorphine and buprenorphine in combination with naloxone administered by: the tablet is kept under the tongue to allow it to dissolve or disperse (usually after a few minutes) without attempting to accelerate the process. CP testing was started about 20 minutes after the completion of administration and continued after that with 1 hour intervals. The compounds are in the form of buprenorphine hydrochloride and naloxone hydrochloride dihydrate. The CP test uses two cylindrical plastic containers, one of which is filled with warm water and the other with a mixture of water and crushed ice, to achieve a "slushy" consistency. Subjects were allowed to immerse the non-conventional forearms and hands in warm water for exactly 2 minutes. At 1 minute 45 seconds, the blood pressure cuff on the immersed arm was inflated to a pressure 20mmHg below the diastolic pressure. The blood pressure cuff minimizes the effect of blood flow in determining a response to cold. At exactly 2 minutes, the forearms were transferred from warm water to a cold water bath. To minimize interference and time implications, the subject's eyes were masked throughout the procedure. Upon immersion of the limb in a cold water bath, the subject was asked to indicate when pain began to be felt (pain threshold, CPTHR) and then asked to immerse the arm until the pain (pain tolerance, CPTOL) was no longer tolerated. The pain threshold and tolerance time were recorded in seconds starting from immersion in cold water. A non-public break of 180 seconds was made after which time the pain tolerance threshold could no longer be accurately assessed due to numbness. In the current study, the pain tolerance threshold (CPTOL) is reported as a pain response parameter.

For this test, nociceptive testing was performed in the same environment, where both background noise and audible sounds were required to be as small as possible, and a clock with an audible click was not available. Ambient room temperature and illumination should be consistent. At no time should the experimenter discuss with the subject his/her performance in the trial, or answer any questions related to the average duration of pain tolerance or any previous results.

The use of these experimental parameters in a series of double-blind studies allows the combination product to achieve a higher degree of analgesia and a longer period of analgesia than buprenorphine alone.

The range of combinations was studied to determine the point at which naloxone levels were too high and antagonized buprenorphine, thereby antagonizing analgesia. In addition, the point was identified where the naloxone content was too low and did not have a synergistic potentiating effect. All naloxone contents between these two points show a favourable potentiating effect of naloxone on buprenorphine.

Claims (10)

1. A composition for use in the treatment of pain in a human patient, wherein the composition comprises buprenorphine and naloxone in a weight ratio of 2.1: 1 to 8: 1, the buprenorphine and naloxone being in amounts suitable to provide analgesia, the composition being in a transdermal or transmucosal dosage form.

2. The composition of claim 1, wherein the ratio is 2.5: 1 to 6: 1, preferably 3: 1 to 5: 1, more preferably 3.5: 1 to 4.5: 1.

3. A composition as claimed in claim 1, wherein the amount of buprenorphine per dosage unit is from 10 μ g to 8 mg.

4. The composition of claim 1, wherein the composition is suitable for oral-nasal administration.

5. A method of treating pain in a human patient, said method comprising transdermally or transmucosally administering to said patient buprenorphine and naloxone in a weight ratio of said buprenorphine to said naloxone of 2.1: 1 to 8: 1.

6. The method of claim 5, comprising sublingual administration.

7. Use of buprenorphine and naloxone in the manufacture of a medicament for the treatment of pain in a human patient, wherein the medicament is for transdermal or transmucosal administration and the buprenorphine and naloxone are provided in the medicament in a buprenorphine to naloxone weight ratio of from 2.1: 1 to 8: 1.

8. The method or use according to claim 5, 6 or 7, wherein said administration typically lasts for a period of 1 to 10 minutes.

9. The method or use of claim 5, 6, 7 or 8, wherein said administration of buprenorphine is from 0.25 to 640 μ g/kg of body weight per 24 hours.

10. A composition or method or use substantially similar to that described in accordance with the present invention.