WO2002087582A1 - Use of the opioid antagonist naltrexone to prevent and control side effects caused by opioids - Google Patents

Use of the opioid antagonist naltrexone to prevent and control side effects caused by opioids Download PDF

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Publication number
WO2002087582A1
WO2002087582A1 PCT/IB2002/001473 IB0201473W WO02087582A1 WO 2002087582 A1 WO2002087582 A1 WO 2002087582A1 IB 0201473 W IB0201473 W IB 0201473W WO 02087582 A1 WO02087582 A1 WO 02087582A1
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WIPO (PCT)
Prior art keywords
naltrexone
side effects
effects caused
morphine
administration
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PCT/IB2002/001473
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French (fr)
Inventor
Roberto Valducci
Tiziano Alighieri
Serozh Avanessian
William Raffaeli
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Valpharma S.A.
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Priority to EP02726358A priority Critical patent/EP1395260A1/en
Publication of WO2002087582A1 publication Critical patent/WO2002087582A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • Opioids are drugs indispensable for the control of severe painful syndromes, but they cause many side effects that, sometimes, render their use by the patients impossible.
  • Valkenberg (Valkenberg H., Epidemiologic considerations of the geriatric population. Gerontology 1988; 34, suppl. 1, 2 - 10) refers that 33% of the population of more than 55 years old suffers from rheumatic pains.
  • pain is present in many other situations like, for example, in the operating and postoperative phase, in AIDS-affected people, etc.
  • opioids are drugs that cause an intense analgesic reaction acting on specific receptors.
  • opioid antagonists Drugs acting on the same receptors without causing any biological effect are defined as opioid antagonists.
  • opioids for example, morphine, codeine and fentanyl can be cited. 5
  • opioid antagonists naloxone, naltrexone and cholecystokinin can be mentioned.
  • the treatment with opioids causes many and severe side effects such as sleepiness, nausea, emesis, constipation, confusion, pruritus, headache, ritention of urine, dysphoric reactions, respiratory depression and myoclonus.
  • patent USP 5580876 A describes the use of morphine combined with the administration of low doses of naltrexone in mouse.
  • Patent application PCT - WO 96/02251 describes the simultaneous intake of morphine and of an opioid antagonist in a ratio antagonist - morphine of 1,0 mg of antagonist per 1 mg of morphine.
  • the ratio antagonist - morphine is fixed while in the clinical practice variable ratios are required in function of the individual reactions of the various patients. Furthermore the aim of said application is restricted to the prevention of addiction.
  • naltrexone administration ranges between 0,01 and 0,9 mg per mg of morphine. Naltrexone is administered by mouth.
  • This invention refers to the use of naltrexone in the preparation of pharmaceutical compositions to be administered by mouth suitable to prevent and control the side effects caused by the opioid therapy.
  • the invention furthermore, refers to a therapeutic method to prevent and control the side effects caused by the treatment with opioids consisting in the administration by mouth of said compositions in quantity equal to 0,01 - 0,9 mg of naltrexone per mg of morphine.
  • the main object of the present invention is to propose a fast, reliable and economic method for the production of tiles with irregular edges having a handcrafted look, starting from plates, consisting of tiles or natural or synthetic slabs.
  • Another object is to propose a method allowing to produce tiles having at least a rectilinear regular edge fit for the joining with other coverings or for carrying out the end portions of covering and having irregular remaining edges.
  • naltrexone for which the clinical experience has demonstrated a great reliability of use also for long periods of administration. Moreover naltrexone has the advantage that it can be administered by mouth.
  • naltrexone is prepared in form of a multiparticulate pharmaceutical composition constituted by pellets of saccharose and starch coated with a polyvinylpyrrolidone and naltrexone layer.
  • said composition has a potency of naltrexone ranging from 0,005 to 0,1 mg per mg.
  • composition is prepared in form of hard gelatine capsules having a content of naltrexone ranging from 0,25 to 0,5 mg per single capsule.
  • composition containing naltrexone is administered half an hour before morphine.
  • the treatment with naltrexone was carried out by administering 0,5 mg by mouth half an hour before the administration of morphine.
  • the treatment with mo ⁇ hine was carried out by administering 10 mg intramuscularly every 12 hours.
  • the side effect incidence and the analgesic efficacy were evaluated by means of internationally accepted and validated questionnaires, utilized to evaluate the variation degrees of the single symptoms. After the first administration of naltrexone, a 60% reduction of the nausea subjective sensation and a 50% reduction of the emesis episodes was noted, while no variation of the analgesic efficacy of the morphine therapy was noted.
  • Naltrexone was administered by mouth half an hour before the administration of mo ⁇ hine, in the dose of 0,25 mg every 12 hours.
  • naltrexone a dose of 0,5 mg of naltrexone was administered every 12 hours, by mouth, half an hour before the administration of mo ⁇ hine. A 50% reduction of said side effects was observed, except for constipation.
  • Example 1 Some examples of multiparticulate preparations are described, suitable for the administration of microdosages of naltrexone.
  • the fluidization of the pellets was realized by means of an airflow having a temperature of 40° C. On the fluidized pellets the following solution was sprayed:
  • pellets were analyzed as for the naltrexone HCl content, which came out to be 0,01 mg / mg. Moreover, the pellets were tested to check the dissolution pattern in water, utilizing the apparatus described in the European Pharmacopoeia - Par. 2.9.3. - Dissolution test for solid dosage forms - "Paddle Apparatus". The value observed was 100%) after 10 minutes.
  • pellets obtained according to this example were encapsulated in hard gelatine capsules.
  • Example 3 A preparation according to the technique of example 1 was carried out, using the following solution:
  • microtablets were dosed in hard gelatine capsules to obtain the dosages of 2,5 and 1,25 mg of naltrexone HCl / capsule.
  • the remaining part of granulate of example 5 was extruded by means of an extruder FUJI PAUDAL DG-L1 having a perforated disc of 0,8 mm and spheronized by means of a spheronizer FUJI PAUDAL Q-230T.
  • the so obtained pellets were desiccated in desiccator at a temperature of 50°C, thus obtaining results similar to those of example 1.

Abstract

Use of naltrexone to prepare pharmaceutical compositions suitable to prevent and control the side effects caused by the treatment with morphine, to be administered by mouth in the dose ranging between 0,01 and 0,9 mg/mg of administered morphine.

Description

USE OF OPIOID ANTAGONISTS TO PREVENT AND CONTROL SIDE EFFECTS CAUSED BY OPIOIDS SE OF THE OPIOID ANTAGONIST NALTREXONE TO PREVENT AND CONTROL SIDE EFFECTS CAUSED BY OPIOIDS
5 TECHNICAL FIELD
The present invention refers to the use of opioid antagonists to prepare compositions suitable to prevent and control the side effects caused by the administration of opioids
0 BACKGROUND ART
Opioids are drugs indispensable for the control of severe painful syndromes, but they cause many side effects that, sometimes, render their use by the patients impossible.
5 Many authors have documented that pain is one of the greatest problem of the public health.
For example, Valkenberg (Valkenberg H., Epidemiologic considerations of the geriatric population. Gerontology 1988; 34, suppl. 1, 2 - 10) refers that 33% of the population of more than 55 years old suffers from rheumatic pains.
0 In the USA it has been evaluated that the cost of the lumbar pains amounts to 50 - 100 billion dollars per year (Frymoyer J.W. and Casta-Baril W.L., "An overview of the incidences and costs of low back pain". Orthop.Clin. N. Am. 1991, 22: 263 - 271).
From the official OMS publications it comes out that pain is present in the 30 - 40% of patients 5 in the starting phase of cancer and in the 60 - 80% in the terminal phase.
Finally, pain is present in many other situations like, for example, in the operating and postoperative phase, in AIDS-affected people, etc.
0 As above stated, the use of opioids is indispensable in the management of severe pain forms. Opioids are drugs that cause an intense analgesic reaction acting on specific receptors.
Drugs acting on the same receptors without causing any biological effect are defined as opioid antagonists. Among the opioids, for example, morphine, codeine and fentanyl can be cited. 5 Among the opioid antagonists, naloxone, naltrexone and cholecystokinin can be mentioned. Unfortunately, the treatment with opioids causes many and severe side effects such as sleepiness, nausea, emesis, constipation, confusion, pruritus, headache, ritention of urine, dysphoric reactions, respiratory depression and myoclonus.
These effects negatively influence the quality of life, particularly in patients under long-term treatment.
Various methods have been proposed to control the side effects of opioids.
For example, for nausea and emesis the use of neuroleptics like haloperidol or droperidol at low doses has been proposed (Cohen S.E. et al., Anestesiology 1984,60:67-9).
Nevertheless these drugs have to be used with caution because of the adverse effects caused by themselves.
The use of opioid antagonists administered simultaneously with the opioids has been proposed with the aim of reducing the development of physical addiction.
For example, patent USP 5580876 A describes the use of morphine combined with the administration of low doses of naltrexone in mouse.
Patent application PCT - WO 96/02251 describes the simultaneous intake of morphine and of an opioid antagonist in a ratio antagonist - morphine of 1,0 mg of antagonist per 1 mg of morphine.
According to this application the ratio antagonist - morphine is fixed while in the clinical practice variable ratios are required in function of the individual reactions of the various patients. Furthermore the aim of said application is restricted to the prevention of addiction.
From the study of the prior art it is evident that the various methods so far proposed to solve the problem of the side effects of the opioid therapy are not satisfactory as they deal only with some of said side effects, or they propose the treatment with drugs that, in their turn, require caution in their administration.
Therefore, the problem of a pharmacological control of the side effects of opioids, maintaining their analgesic efficacy, remains open. DISCLOSURE OF THE INVENTION
Now we have found that the treatment with very low doses of an opioid antagonist like naltrexone in patients under opioid treatment allows to obtain a significant global reduction of the opioid side effects, by maintaining the analgesic efficacy of opioids themselves.
The naltrexone administration according to this invention ranges between 0,01 and 0,9 mg per mg of morphine. Naltrexone is administered by mouth.
This invention, therefore, refers to the use of naltrexone in the preparation of pharmaceutical compositions to be administered by mouth suitable to prevent and control the side effects caused by the opioid therapy.
The invention, furthermore, refers to a therapeutic method to prevent and control the side effects caused by the treatment with opioids consisting in the administration by mouth of said compositions in quantity equal to 0,01 - 0,9 mg of naltrexone per mg of morphine.
The main object of the present invention is to propose a fast, reliable and economic method for the production of tiles with irregular edges having a handcrafted look, starting from plates, consisting of tiles or natural or synthetic slabs.
Another object is to propose a method allowing to produce tiles having at least a rectilinear regular edge fit for the joining with other coverings or for carrying out the end portions of covering and having irregular remaining edges.
The above-mentioned object are achieved according with the content of the claims.
BEST MODE OF CARRYING OUT THE INVENTION
The characteristics and the advantages of the use of opioid antagonists to prevent and control the side effects caused by opioids will be better explained in the following detailed description.
The preferred opioid antagonist is naltrexone, for which the clinical experience has demonstrated a great reliability of use also for long periods of administration. Moreover naltrexone has the advantage that it can be administered by mouth.
We have found that the administration of a dose ranging from 0,01 to 0,9 mg of naltrexone per mg of morphine allows to significatively reduce the side effects of moφhine maintaining unchanged the analgesic activity of moφhine.
Preferably naltrexone is prepared in form of a multiparticulate pharmaceutical composition constituted by pellets of saccharose and starch coated with a polyvinylpyrrolidone and naltrexone layer. Preferably said composition has a potency of naltrexone ranging from 0,005 to 0,1 mg per mg.
Preferably said composition is prepared in form of hard gelatine capsules having a content of naltrexone ranging from 0,25 to 0,5 mg per single capsule. Preferably the composition containing naltrexone is administered half an hour before morphine.
The invention is explained by the following clinical experimentation.
CLINICAL EXAMPLES
1) Five patients with persistent nausea and emesis non-reacting to metoclopramide, caused by the administration of moφhine to control the postoperative pain, were treated with a composition of naltrexone prepared according to example 1.
The treatment with naltrexone began after 2 days of treatment with moφhine.
The treatment with naltrexone was carried out by administering 0,5 mg by mouth half an hour before the administration of morphine.
The treatment with moφhine was carried out by administering 10 mg intramuscularly every 12 hours.
The side effect incidence and the analgesic efficacy were evaluated by means of internationally accepted and validated questionnaires, utilized to evaluate the variation degrees of the single symptoms. After the first administration of naltrexone, a 60% reduction of the nausea subjective sensation and a 50% reduction of the emesis episodes was noted, while no variation of the analgesic efficacy of the morphine therapy was noted.
2) 10 mg of moφhine every 12 hours were intramuscularly administered to five patients in postoperative phase with analgesic aim. To the same patients a dose of 0,5 mg of naltrexone was administered half an hour before every administration of moφhine.
With this treatment the onset of the side effects of moφhine was prevented in three patients and, in the other two patients, the intensity and the frequency of such effects turned out to be of moderate degree.
3) Fifteen patients affected by pain of osteogenic origin, secondary to multiple vertebral collapses from primary osteoporosis, who showed side effects (ritention of urine, pruritus, nausea, emesis, inappetence and constipation) due to the administration of 2 mg of moφhine every 12 hours per epidural way, were treated with naltrexone.
Naltrexone was administered by mouth half an hour before the administration of moφhine, in the dose of 0,25 mg every 12 hours.
Five patients showed a total remission of the side effects, except for constipation. The other ten patients showed a 60% reduction of the side effects.
4) Twelve patients with pain of metastasized cancer showed nausea, emesis, pruritus and constipation caused by the intake of moφhine in the dose of 30 mg every 12 hours.
To said patients a dose of 0,5 mg of naltrexone was administered every 12 hours, by mouth, half an hour before the administration of moφhine. A 50% reduction of said side effects was observed, except for constipation.
EXAMPLES OF COMPOSITIONS CONTAINING NALTREXONE
Some examples of multiparticulate preparations are described, suitable for the administration of microdosages of naltrexone. Example 1
1 Kg of pellets constituted by saccharose and starch in a weight ratio of 75/25, having granulometry ranging from 0,7 to 1,1 mm, was put in fluid bed UNIGLATT produced by the company Glatt GmbH.
The fluidization of the pellets was realized by means of an airflow having a temperature of 40° C. On the fluidized pellets the following solution was sprayed:
- naltrexone HCl 0,100 g water 100 g - ethanol 100 g
- PVP at 20% in ethanol 50 g
The so obtained pellets were analyzed as for the naltrexone HCl content, which came out to be 0,01 mg / mg. Moreover, the pellets were tested to check the dissolution pattern in water, utilizing the apparatus described in the European Pharmacopoeia - Par. 2.9.3. - Dissolution test for solid dosage forms - "Paddle Apparatus". The value observed was 100%) after 10 minutes.
The pellets obtained according to this example were encapsulated in hard gelatine capsules. Capsules containing 50 mg of pellets equivalent to 0,5 mg of naltrexone HCl and capsules containing 25 mg of pellets, equivalent to 0,25 mg of naltrexone HCl, were prepared.
Example 2
2 Kg of pellets constituted by saccharose and starch, like in example 1, were put in a rotating pan and onto said pellets the following solution was sprayed:
- naltrexone HCl 0,200 g water 200 g
- ethanol 200 g
- PVP at 20% in ethanol 50 g
The above described pellets were analyzed as per example 1 obtaining results similar to those of example 1.
Example 3 A preparation according to the technique of example 1 was carried out, using the following solution:
- naltrexone HCl 0,100 g
- water 200 g - PVP at 20% in ethanol 1 g
The obtained pellets were analyzed obtaining results similar to those of Example 1.
Example 4
A test as per example 3 was carried out, replacing water with ethanol, thus obtaining the same results.
Example 5
In a VIANI granulator model ST25 the following components were mixed: lactose 2,0 Kg microcrystalline cellulose 3,0 Kg
The above-indicated mixture was wet with 0,6 Kg of a solution compounded as follows: - naltrexone HCl 0,500 g
- PVP at 20% in water 599,5 g
About 2 Kg of the above indicated granulate were put in desiccator; then, the granules were mixed with 0,5%) of magnesium stearate and tableted to obtain microtablets with a diameter of 2 mm.
The so obtained microtablets were dosed in hard gelatine capsules to obtain the dosages of 2,5 and 1,25 mg of naltrexone HCl / capsule.
The remaining part of granulate of example 5 was extruded by means of an extruder FUJI PAUDAL DG-L1 having a perforated disc of 0,8 mm and spheronized by means of a spheronizer FUJI PAUDAL Q-230T. The so obtained pellets were desiccated in desiccator at a temperature of 50°C, thus obtaining results similar to those of example 1.

Claims

1) Use of naltrexone to prepare pharmaceutical compositions suitable to prevent and control the side effects caused by the treatment with moφhine, to be administered by mouth in the dose ranging between 0,01 and 0,9 mg / mg of administered morphine.
2) Pharmaceutical compositions in multiparticulate form suitable to control the side effects caused by the treatment with morphine characterized by the fact of being constituted by pellets of saccharose and starch coated with a polyvinylpyrrolidone and naltrexone layer.
3) Compositions according claim 2, wherein the naltrexone content ranges between 0,005 and 0,1 mg / mg of composition.
4) Compositions according to claim 2, prepared in form of hard gelatine capsules having a naltrexone content ranging from 0,25 to 0,9 mg per single dose of composition.
5) Therapeutic method to control the side effects caused by the treatment with morphine consisting in the administration by mouth of a composition according to claim 2 in a quantity ranging from 0,01 to 0,9 mg of naltrexone per mg of moφhine.
6) Method according to claim 5, wherein said administration of naltrexone is carried out half an hour before the administration of moφhine.
PCT/IB2002/001473 2001-05-02 2002-05-02 Use of the opioid antagonist naltrexone to prevent and control side effects caused by opioids WO2002087582A1 (en)

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ITMI2001A000907 2001-05-02
IT2001MI000907A ITMI20010907A1 (en) 2001-05-02 2001-05-02 USE OF OPIOID ANTAGONISTS FOR THE PREVENTION AND CONTROL OF THE SIDE EFFECTS PRODUCED BY THE OPIOIDS

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