HK1139871B - Improvements in and relating to medicinal compositions - Google Patents

Description

Improvements in and relating to pharmaceutical compositions

Technical Field

The present invention relates to pharmaceutical compositions containing buprenorphine in combination with naloxone; and to the use of buprenorphine and naloxone in the manufacture of said compositions and as analgesics in clinical practice.

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. However, it has been found that co-administration of antagonists may in some cases potentiate antinociception.

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

In GB 2150832A an analgesic composition of parenteral or sublingual form is disclosed 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. The parenteral dosage form may comprise buprenorphine and naloxone in a weight ratio of 3: 1 to 1: 1, and the sublingual form may comprise buprenorphine and naloxone in a weight ratio of 1: 2 to 2: 1. The test in GB-A-2150832 was carried out on rats.

In EP 1242087A it is disclosed that low doses of naloxone can potentiate and increase parenteral and sublingual levels of buprenorphine. According to testing in rats, suitable weight ratios of buprenorphine to naloxone are shown to be 12.5: 1 to 27.5: 1, preferably 15: 1 to 20: 1.

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 an analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa or dermis, the composition comprising buprenorphine and an amount of naloxone such that the ratio by weight of buprenorphine to naloxone delivered to or reaching the plasma of a patient is from 7.5:1 to 12.4: 1.

It is believed that the analgesic action of buprenorphine is potentiated by the relatively small amount of naloxone.

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 described herein refer to the proportion and weight of buprenorphine to naloxone itself, and not to the proportion and weight of the salt, base or ester.

The term "parenteral" is intended to encompass administration of the composition by any means other than through the digestive tract.

The term "mucosa (mucosa)" is intended to encompass any mucomembranous membrane (mucous membrane) and includes oral mucosa, rectal mucosa, vaginal mucosa and nasal mucosa. The term "dermis" refers to non-mucosal skin.

Application may take several minutes, depending on its nature. The application is preferably carried out for at least 1 minute, more preferably for at least 2 minutes, more preferably for at least 3 minutes. The application is preferably carried out for up to 10 minutes, more preferably for up to 7 minutes, more preferably for up to 5 minutes.

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.

Preferably, the defined ratio of buprenorphine to naloxone is achieved within 60 minutes after completion of the administration; that is, it is preferred that the defined drug ratio in plasma is achieved at some point within 60 minutes of completion of administration.

The composition may comprise buprenorphine and naloxone such that the weight ratio of buprenorphine to naloxone delivered to or reaching the plasma of the patient is at least X: 1(X to 1), wherein X is 8.0, preferably 9.0, more preferably 9.5, more preferably 10.0, more preferably 10.5, more preferably 11.0.

The composition may comprise buprenorphine and naloxone such that the weight ratio of buprenorphine to naloxone delivered to or reaching the plasma of the patient is no more than Y: 1(Y to 1), wherein Y is 12.3, preferably 12.2, more preferably 12.0, more preferably 11.5.

Surprisingly, it has been found that although the relative amount of naloxone to buprenorphine in the present invention is higher than in EP 1242087B, the antagonist effect of naloxone does not "win" and indeed naloxone potentiates the agonist effect of buprenorphine.

The composition may comprise a parenteral unit dosage form and the ratio of buprenorphine to naloxone in the parenteral composition may be substantially the same as the ratio which reaches or is delivered to the plasma of a patient at the time of use. Thus, the parenteral dosage form may contain buprenorphine and naloxone in a weight ratio of 7.5:1 to 12.4:1, with the preferred upper and lower limits of this ratio being the same as those described above for buprenorphine and naloxone in plasma.

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, the same analgesic effect can be achieved with a lower dose of buprenorphine when combined with naloxone. 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, the compositions of the present invention comprise at least 10 μ g of buprenorphine per unit dose, 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. 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 body weight per 24 hours. Preferably the amount is at least 0.05 μ g/kg body weight, more preferably at least 0.1 μ g/kg body weight, more preferably at least 0.15 μ g/kg body weight, more preferably at least 0.2 μ g/kg body weight, more preferably at least 0.25 μ g/kg body weight, more preferably at least 0.4 μ g/kg body weight.

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. mu.g/kg 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.

Preferably, the compositions are formulated in unit dosage form, i.e. physically discrete units containing appropriate amounts of buprenorphine and naloxone, together with pharmaceutically acceptable diluents and/or carriers. The unit dosage form for parenteral administration is suitably in the form of an ampoule. 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 described in the second aspect, may comprise delivery of a medicament comprising buprenorphine and naloxone, preferably in such a form.

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 in the form of sublingual dosage forms suitably comprise soluble excipients selected from substances such as lactose, mannitol, dextrose, sucrose and the like or mixtures thereof. They also suitably comprise granulating and disintegrating agents selected from materials such as starch, binding agents such as povidone or hydroxypropylmethylcellulose and lubricating agents such as magnesium stearate.

Compositions for parenteral administration may comprise isotonic solutions of buprenorphine and naloxone in sterile water. Typically, the solution can be made isotonic by using dextrose and sterilized by autoclaving or filtration through a membrane filter. The composition can be administered by intramuscular, intradermal, intraperitoneal, intravenous, intraarterial, subcutaneous, or epidural routes.

As described in detail above, compositions for parenteral administration or for transmucosal delivery, such as by sublingual administration, 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 a method of treating pain in a human patient, the method comprising administering buprenorphine and naloxone to the human patient by parenteral or dermal or mucosal route such that the ratio by weight of buprenorphine to naloxone delivered to or reaching the plasma of the patient is from 7.5:1 to 12.4: 1.

Preferred ratios of buprenorphine to naloxone are as defined above for the first aspect.

Suitably, the method comprises delivery via the mucosa. The method may include delivery in a sublingual unit dosage form.

Suitably, the method comprises administering buprenorphine and an amount of naloxone which is achievable for the purpose of potentiating the analgesic effect of the buprenorphine, in particular to optimise the balance between the analgesic effect of the buprenorphine and the abuse-resistant effect of the naloxone. It will be appreciated that this balance is extremely important. The agent must be an effective analgesic to perform its intended function. At the same time, it is also currently of paramount importance to prevent the abuse of opioid drugs by addicts. The present invention is believed to be extremely effective in these respects.

Separate administration of buprenorphine and naloxone is not excluded from the method. Suitably, however, the method comprises administering to the human a composition comprising buprenorphine and naloxone. Suitably, the method uses a composition of the first aspect. The definitions given above for the first aspect apply to the second aspect, although it is noted that buprenorphine and naloxone may in principle be administered separately in the second aspect.

Suitably, the method comprises administering to the human or animal from 0.25 μ g/kg body weight to 20 μ g/kg body weight of buprenorphine per day.

The method may comprise administering a dose of buprenorphine that produces minimal or no antinociception when administered alone. The method may comprise administering to a human buprenorphine and naloxone in amounts as described above in relation to the first aspect of the invention.

The method may comprise any of the features as described in the first aspect.

According to a third aspect of the present invention there is provided the use of naloxone and buprenorphine in the manufacture of a medicament for the treatment of pain, wherein the naloxone and buprenorphine are used in amounts such that the medicament is delivered to a patient or in the plasma of a patient to achieve a buprenorphine to naloxone weight ratio of from 7.5:1 to 12.4: 1.

Suitably, the use comprises the use of buprenorphine and naloxone in the manufacture of a medicament for the treatment of pain, wherein buprenorphine is used for its analgesic effect, but at a level which is lower than would be required to provide a given analgesic effect for a given pain in a given patient in the absence of naloxone. Thus, naloxone can potentiate the analgesic effect of buprenorphine. In addition, it also makes the medicament less attractive (preferably completely unattractive) to drug addicts.

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

Suitably, the use of buprenorphine and naloxone in the manufacture of a medicament comprises the manufacture of a medicament comprising a composition of the first aspect. However, the use of buprenorphine and naloxone in the manufacture of a medicament having two dosage units comprising buprenorphine and naloxone, respectively, is not excluded.

Drawings

The invention will now be described, by way of example, with reference to the accompanying drawings, in which:

FIG. 1 is a graph of pain threshold resistance results for a combination of buprenorphine and naloxone;

figure 2 is a graph of the pain threshold resistance results for buprenorphine alone; and

fig. 3 is a graph of comparison.

Detailed Description

Method of producing a composite material

Nociceptive testing

The cold Compression (CP) test was used to evaluate the antinociception of buprenorphine and buprenorphine in combination with naloxone. The compounds are in the form of buprenorphine HCl and naloxone HCl 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.

Screening

Prior to testing, subjects were screened according to inclusion and exclusion criteria based on factors such as previous medical conditions and drug abuse.

Test procedure

The screened suitable subjects were tested according to the following procedure. Subjects provided a urine sample upon arrival on the day of testing, which was tested for drugs of abuse (opioids, cannabinoids, benzodiazepines and sympathomimetic amines) and for pregnancy in female subjects. A 22 gauge indwelling venous catheter was inserted into the most easily inserted forearm vein of each arm (above the CP infusion line for the non-dominant arm). An injection site (male luer lock adaptor) of a male luer lock adapter was connected to each catheter. One catheter was used for blood sampling throughout the test day and the other catheter was used for infusion. The participant is then connected to a monitor that is set to continuously monitor the physiological parameter during the testing session.

On each test day, subjects received a 30 minute non-blind intravenous saline infusion followed by one or more 30 minute drug (or placebo) infusions. The initial saline infusion has a dual purpose: determining whether there is any change in pain or physiological parameter that occurs in response to the infusion process itself, and ensuring that there is no obstruction of the venous access via the catheter and that the infusion pump is functioning properly.

Infusion was performed using a syringe pump. The drug and saline were prepared in 30ml BD Plastipak syringes. Infusion was performed at a rate of 20 ml/hour for 30 minutes. Each syringe was connected to a minimum volume extension set (150cm tube, female luer lock, male luer lock, 0.5mL/30 cm). The male luer lock fitting is attached to a lever lock cannula (lever lock cannula). The extension set was perfused with drug/saline and inserted into the injection site. In the buprenorphine: antagonist ratio study, BUP was administered concurrently with the antagonist. For simultaneous infusion of two drugs (through one cannula), a Y-shaped catheter extension set with two injection sites can be attached to the catheter and a rod lock cannula (attached to each syringe through a minimum volume extension set) inserted into each injection site.

The testing activities are performed at a number of different occasions on each test day. Each test activity consists of the following measurements performed in the following order: recording nausea and sedation, drawing blood samples, recording physiological parameters (pulse, oxygen saturation and blood pressure), completing nociceptive testing (as detailed above), and recording respiration (number of breaths per minute counted for a complete minute during the warm water portion of the CP).

On each test day, test activities were performed at set intervals. These test activities are as follows; 1. before infusion begins; 2. 20 minutes after the start of the saline infusion at 30 minutes; 3. 20 minutes after the start of the 30 minute drug infusion and every hour after the termination of the (last) drug infusion. This is called a purge period. The purpose of performing the test activity 20 minutes after the start of each 30 minute infusion is to allow time for the test to be completed before the start of the subsequent infusion.

Comparison of results

As baseline values varied between conditions, CPTOL data were expressed as percent change from baseline in order to compare the effects associated with different drug combinations. The response of each participant at each time point for each condition was expressed as a percent change from the baseline response according to the following equation. Data can be expressed as mean (± SEM) of these values for each post-dose testing activity under each condition.

This provides a value for the percentage change in CPTOL.

Examples

Example 1

8 healthy caucasian volunteers (4 men and 4 women) participated in the study. Data from a 37 year old male was not used in the analysis because the urine was opioid positive on the test day with BUP alone. Thus, the final sample (n ═ 7) included 3 men and 4 women, with a mean age of 25.14 years (+ -1.02, range of 21-37 years), and a mean CPTOL of 43.00 for the screen (+ -6.73, range of 29-80). There was no significant difference between men and women in age (p ═ 0.265) or screened CPTOL (0.764).

Buprenorphine and naloxone were administered to subjects by IV infusion at a ratio of 10: 1, the dose of buprenorphine administered being 0.5 μ g/kg body weight. Clearance monitoring was performed for a period of 10 hours. CPTOL results are shown in FIG. 1. No noticeable adverse reactions were found.

Example 2 comparison

As a comparative example, on a separate day, the same subjects in example 1 were administered buprenorphine and saline by IV infusion (hereinafter referred to as "BUP only"). Buprenorphine was still administered at a dose of 0.5 μ g/kg body weight and clearance monitoring was performed for 10 hours. CPTOL results are shown in FIG. 2.

Comparison of examples

The percent change in CPTOL for examples 1 and 2 from baseline was calculated and the results are shown in fig. 3. It can be found that the combination of buprenorphine and naloxone is advantageous compared to buprenorphine alone for the earlier hours in the trial.

Example 3 parenteral composition

A parenteral formulation having the following composition is prepared by dissolving dextrose, buprenorphine hydrochloride and naloxone hydrochloride sequentially in about 95% bulk (batch volume) of water for injection with stirring:

the acidity of the solution was adjusted to pH 4.0 by adding 0.1M hydrochloric acid and the solution was brought to the volume using water for injection. The solution was filtered through a membrane filter and transferred to a sterilized 2ml glass ampoule containing 2ml of the solution. The ampoule is sealed and the product is sterilized by autoclaving.

EXAMPLE 4 Sublingual compositions

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.

Claims (5)

1. An analgesic composition in parenteral unit dosage form or in a unit dosage form suitable for delivery via the mucosa or dermis, the composition comprising from 10 μ g to 8mg of buprenorphine and from 1 μ g to 4mg of naloxone such that the ratio by weight of buprenorphine to naloxone delivered to or reaching the plasma of a patient is from 7.5:1 to 12.4: 1.

2. The composition of claim 1, wherein the ratio is at least X:1, wherein X is 8.0 or 9.0 or 9.5 or 10.0 or 10.5 or 11.0.

3. A composition according to claim 1 or 2, wherein the ratio is at most Y: 1, wherein Y is 12.3 or 12.2 or 12.0 or 11.5.

4. Use of naloxone and buprenorphine in the manufacture of a medicament for the treatment of pain, wherein the amount of naloxone is in the range of from 1 μ g to 4mg and buprenorphine is in the range of from 10 μ g to 8mg in a unit dosage form such that the medicament is delivered to a patient or in the plasma of a patient to achieve a buprenorphine to naloxone weight ratio of from 7.5:1 to 12.4: 1.

5. Use as claimed in claim 4, wherein the administration of buprenorphine is from 0.25 to 640 μ g/kg of body weight per 24 hours.