WO2007022609A1 - Pharmaceutical composition of morphine in ready-to-use injectable solution form and single dosage form of morphine for epidural or intrathecal administration - Google Patents
Pharmaceutical composition of morphine in ready-to-use injectable solution form and single dosage form of morphine for epidural or intrathecal administration Download PDFInfo
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- WO2007022609A1 WO2007022609A1 PCT/BR2006/000168 BR2006000168W WO2007022609A1 WO 2007022609 A1 WO2007022609 A1 WO 2007022609A1 BR 2006000168 W BR2006000168 W BR 2006000168W WO 2007022609 A1 WO2007022609 A1 WO 2007022609A1
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- 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
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
Definitions
- the present invention describes morphine diluted pharmaceutical compositions, bottled in amber glass ampoules, vials or syringes for single doses or in plastic bags. More specifically, the present invention describes a morphine diluted pharmaceutical formulation, in ready-to-use form, appropriated for administration via epidural or intrathecal routes in adults, or via intravenous route in children, in pre- and post-surgical procedures delivering a sufficient and safe dosage of the drug.
- Morphine is included in the pharmacological group of opioid analgesics, and placed among the most potent narcotic agents of clinical use, which produce depression of the Central Nervous System (CNS) .
- the analgesic and depressing effects of such drug occur through the interaction with CNS ⁇ -opioid receptors, referred as responsible for the effects of analgesia, euphoria, potential of addiction and breathing depression, and kappa receptors, also of the CNS that mediates the spinal analgesia, myosis and sedation, altering responses to pain and eliminating anxiety and apprehension.
- This drug is mainly used for relief of moderately severe to severe pain (for example, cancer pain) , myocardial infarct associated pain, post-surgery pain and dyspnea associated to left ventricular acute insufficiency and lung edema, and suppression of severe cough and severe diarrhea (for example, the one caused by cholera) .
- compositions of morphine sulfate are commercially available in the injection (0.2 mg/mL to 50 mg/mL) , capsule (15 and 30 mg) , tablet (10, 15 and 30 mg) , sustained release tablet (15, 30, 60, 100 and 200 mg) , oral solution (2 mg/mL to 20 mg/mL) and rectal suppositories (5, 10, 20 and 30 mg) forms.
- the dosages used for the treatments involving morphine vary with the administration route, due to the differences in bioavailability: intravenous (100%), oral (33%), transmucosal (30-60%) and rectal (30-40%) .
- the usual dosage range is from 5 to 20 mg/70 Kg at every 4 hours, depending on pain severity. Dosages of 10 mg/70 Kg at every 4 hours via intramuscular route are used for moderate to severe pains.
- the oral dosage usually ranges from 8 to 20 mg, but under oral administration, morphine has substantially lower analgesic power (approximately 1/10 of the effect produced by subcutaneous injection) due to its fast degradation when passing through liver, immediately after its absorption.
- the intravenous administration route is primarily employed in severe post-surgery pain or in emergencies; in this case the dosage range may be comprised from 2 to 10 mg for the analgesic effect.
- the epidural, intrathecal (or subarachnoid) administration or morphine infusion may be employed on patients that present refractory pain.
- intrathecal administration the usual dosage range is from 0.2 to 1 mg, which is able to provide satisfactory pain relief for up to 24 hours.
- Morphine may also be combined with other non-opioid analgesics or with psychotropic drugs.
- Morphine is a hydrophilic opioid that promotes intense and long lasting analgesia. For being hydrophilic, its action duration is extended, however, this characteristic is also responsible for drug permanence in the liquor for a period longer than with a lipophilic opioid. Thus, a larger opioid diffusion occurs to the cranial region, which can provoke side effects such as itching, nausea, vomit and breathing depression. The presence of such side effects limits the use of morphine by spinal route.
- morphine dosages of morphine are efficient for reducing the post-surgery pain of patients submitted to cesarean, with lower incidences of side effects.
- the morphine dosage recommended for administration in the subarachnoid space is 0.1 mg [Dahl JB, Jeppesen IS, Jorgensen H et al Anesthesiology, 1999; 91:1919-1927; Palmer CM, Emerson S, Volgoropolous D et al Anesthesiology, 1999; 90 : 437-444] , however, there are clinical works showing that morphine would achieve its maximum effect with dosages lower than 0.1 mg [Sibilla C, Albertazzi P, Zateli R et al, Int J Obstet Anaesth, 1994; 3:203- 207]. However, some authors found that 0.1 mg of morphine was efficient for blocking pain only when associated with other analgesics [Swart M, Swell J, Thomas D, Anaesthesia, 1997 / 52:364-381]
- morphine in the dosage of 0.025mg via subarachnoid route, associated with other non-steroidal anti-inflammatory drugs (diclofenac) , provided a good analgesia quality, with minimal side effects [Cardoso MMSC, Carvalho JCA, Amaro AR et al, Anesth Analg, 1998; 86:538-541] .
- Ganem EM et al. [GANEM EM, MODOLO NSP, FERRARI F, CORDON FCO, KOGUTI ES, CASTIGLIA YMM., Rev Bras Anest 53 (4) : 431-439.2003] have evaluated the quality of post-surgery analgesia and the occurrence of side effects in patients submitted to cesareans, under subarachnoid anesthesia with hyperbaric bupivacaine and morphine in dosages of 0.05 mg and 0.1 mg, associated to ketoprofen via intravenous and oral route.
- morphine dosages of 0.05 mg and 0.1 mg associated to ketoprofen were considered efficient for blocking the pain during the first 12 hours of post-surgery and, after 24 hours of surgery, the pain was of mild intensity. What can be observed on the side effects of morphine is that, even with small dosages, some patients presented symptoms of itching, nausea and vomit episodes
- Hirahar JT et al. [HIRAHAR JT. BLIACHERIENE S, YAMAGUCHI ET, ROSA MCR, CARDOSO MMSC, Rev Bras Anest 53 (6) : 737-742. 2003], have demonstrated that the administration of diclofenac via muscular route or ketoprofen via intravenous route, when combined with low dosage of morphine via subarachnoid route, promotes similar quality post-surgery analgesia in cesareans.
- the multimodal association for pain control has already been emphasized as a way to improve the efficacy of analgesia through drugs with different action mechanisms.
- the association of 0.1 mg or 0.05 rag of morphine with diclofenac or ketoprofen has been elected as a good option for treating post-cesarean pain, due to the fact that the drugs excretion in maternal milk in these dosages is safe for the neonate, allowing immediate suckling [CARDOSO MM - Letters to the Editor, Rev Bras Anest jul-ago 54 (4) : 621-622, 2004] .
- Patent US 5,589,480 filed on August 17, 1994, refers to the use of a diluted solution of analgesic opioid drugs, such as morphine, specifically morphine sulfate, approaching method and apparatus for the topic administration of such drugs, in sufficient concentration to produce analgesic effect in a located area, typically swollen, without opioid drug migration into the blood circulation.
- analgesic opioid drugs such as morphine, specifically morphine sulfate
- the drug acts on opioid receptors found in peripheral tissues, preventing undesirable effects that occur through the activation of receptors located in the brain, mainly the addiction.
- a single dose is equivalent to 3 mg of morphine per 6 square inches of affected area.
- Patent US 5,919,473, filed on May 12, 1997 refers to a drug release device for intradermal administration containing an analgesic agent, among them the morphine and a polymeric material. Such device releases the analgesic for at least 1 day through a surgical stitching and the amount of drug is insufficient to produce CNS mediated analgesia.
- the amount of morphine in one single dosage may range from 0.01 mg/4h/10cm to 8mg/4h/10cm of wound.
- This invention also describes a method for treatment of post-surgery pain associated to wounds or swollen/painful areas, by means of the device described above.
- the international application WO 98/16197 refers to a medicinal paste containing an opioid analgesic (10-500mg), especially morphine, and a microfibrillar collagen (100- lOOOmg) , for use in a surgical procedure to reduce pain.
- the paste is directly administered in the epidural space and significantly improves the control of lumbar post-surgical pain.
- the paste may contain, in association with the analgesic agent, an anti-inflammatory, preferably a steroid.
- the examples of formulation for the favorite pastes of this invention use 3-5mg of Epimorph®.
- Patent JP 6239746 filed on February 12, 1993, refers to a preparation of morphine sustained release, which contains morphine microcapsules ( ⁇ lOO ⁇ m) , formed from a morphine solution, a medium containing a contrast, an amino acid, an amide or a higher alcohol, in a sodium chloride solution for injection, artificial spinal fluid or local anesthetic.
- morphine sustained release which contains morphine microcapsules ( ⁇ lOO ⁇ m) , formed from a morphine solution, a medium containing a contrast, an amino acid, an amide or a higher alcohol, in a sodium chloride solution for injection, artificial spinal fluid or local anesthetic.
- Such preparation is injected in the subarachnoid cavity or epidural space.
- the preparation is especially used for cancer pain relief providing efficient levels of morphine in the blood for about 100 days after an infusion.
- This document refers to a formulation containing an opioid, such as morphine, in concentration lower than 2 mg, preferably 1 mg, in a drug- release controlling carrier.
- the carrier may be a gel, micro-particles or implant, preferably a gel, such as carbohydrate polymer gel ADCON ⁇ -L, which acts as a barrier for the development of epidural fibrosis, originating from lumbar procedures, besides controlling the drug release.
- the formulation of this invention has the purpose of pain treatment for a period of one or more days after spinal cord surgery and/or other structures associated with the Central Nervous System.
- the international application WO 97/03652 refers to a sustained release formulation of an opioid therapeutic agent, such as morphine sulfate for epidural administration.
- the opioid which is encapsulated within the non-concentric aqueous double-layers of multivesicular liposome is released for a long period of time when the liposomes are introduced through epidural route, as a single dose for continued analgesia.
- compositions containing a combination of an opioid antagonist and an opioid agonist for neuropathic pain relief are included.
- naltrexone and morphine nalmephene and morphine
- naloxone and morphine naltrexone and morphine
- Naltrexone, nalmephene or naloxone amount ranges from 0.000001 mg to 1.0 mg
- morphine amount ranges from 0.1 mg to 300 mg.
- the active ingredients may be combined with a sterile aqueous solution.
- Patent US 5,346,903 refers to a preparation for injection in aqueous suspension form containing a local anesthetic and/or water-insoluble narcotic analgesic (1 to 15% in weight, which is, from 10 to 150 mg/mL) suspended in an aqueous medium, with the suspension being stabilized by a non-ionic surfactant agent.
- a method for preparing the suspension and the use of this preparation in epidural, intrathecal, conduction and infiltration anesthesia is also described.
- the average particles diameter of the active agent is less than 20 ⁇ m.
- a stable suspension may be produced from 1 g of powder form morphine, having a particle size of 15 ⁇ m using 10 mL of a 0.9% NaCl solution containing 2.5 mg of polissorbate 80 (about 0.025% by weight).
- the product Depodur® is a sterile multivesicular liposome suspension containing morphine sulfate in 0.9% NaCl solution for epidural administration.
- Each vial contains 10 mg/mL of morphine sulfate (expressed as pentahydrate) and the inactive ingredients include 1, 2-dioleoyl-sn-glycero-3- phosphocholine, cholesterol, 1, 2-dipalmitoyl-sn-glycero-3- phospho-rac (1-glycerol) , tricaprylin and triolein.
- morphine sulfate expressed as pentahydrate
- the inactive ingredients include 1, 2-dioleoyl-sn-glycero-3- phosphocholine, cholesterol, 1, 2-dipalmitoyl-sn-glycero-3- phospho-rac (1-glycerol) , tricaprylin and triolein.
- Patent US 5,723,147 refers to a multivesicular liposome containing a biologically active substance encapsulated in the presence of a hydrochloride that is used for modulating the release rate of the encapsulated active.
- This document describes a multivesicular liposome composition containing an active compound, such as morphine sulfate (expressed as pentahydrate) , an amphipathic lipid, a neutral lipid and hydrochloric acid.
- Patent US 6,310,072 describes an analgesic composition containing a sub-analgesic dosage of an agonist opioid of ⁇ - receptor, such as morphine or pharmaceutically acceptable salts thereof, and a sub-analgesic dosage of oxycodone which is an opioid agonist of kappa-receptor.
- the dosages of morphine and oxycodone are specified on account of the administration route, if the patient is an adult or a child, and if the dosage form is of immediate or sustained release.
- the lower morphine dosage range reported is from 0.05 to 0.25 mg per day, for intracerebral ventricular administration .
- Patent literature reveals several approaches related to the use of morphine, but still there is a lack of simple, safe and efficient alternatives in the area of surgery and post-surgery pain treatment.
- the objective of the present invention is to propose diluted presentations of morphine, appropriate for continuous, intravenous, intrathecal or epidural analgesia, or in analgesia controlled by the patient.
- Morphine is usually administered in the form of morphine sulfate, although hydrochloride and tartarate salts thereof may also be used in similar doses.
- the analgesic composition of the present invention is in the injectable solution form, apyrogenic and sterile, which is constituted of a pharmaceutically acceptable morphine salt dissolved in a pharmaceutically acceptable solvent (carrier) , being the pH of the resulting solution in the range of 2.5 to 6.5 and the morphine concentration is of about 0.0188 to 0.1466 mg/mL (expressed as free base).
- a pharmaceutically acceptable solvent carrier
- the morphine concentration in the composition of the present invention is from 0.025 to 0.195 mg/mL (expressed as sulfate or hydrochloride hydrated salt thereof) .
- morphine is used in the form of pharmaceutically acceptable salts thereof, selected from the group consisting of morphine sulfate and morphine hydrochloride, either the anhydrous or the hydrated.
- the morphine concentration in the resulting solution ranges from 0.025 to 0.195 mg/mL.
- the morphine concentration ranges from 0.05 to 0.1 mg/mL (expressed as sulfate or hydrochloride hydrated salt thereof) .
- the solvent (carrier) of the composition of the present invention is selected from a group consisting of water for injection, physiological saline solution, artificial spinal fluid and local anesthetics solutions.
- the carrier is preferably 0.9% physiological solution, but other diluents may equally be applied in the preparation of the formulation like for example, water for injection, glucose or dextrose solution, artificial spinal fluid or local anesthetics solutions.
- the pharmaceutical composition of the present invention is free of antioxidants, preservatives or other potentially neurotoxic additives.
- a pharmaceutical composition containing morphine, in diluted aqueous solution and ready-to-use form, which enables the direct use of this drug, with no need of previous preparation.
- diluted solution means that low dosages of morphine are administered to the patient, when compared with the dosages previously administered in solution or in a carrier that does not provide sustained release.
- the presentation form of the present invention composition provides the appropriate pharmaceutical form for morphine administration and achievement of the desired therapeutic effect.
- pharmaceutical form refers to the final state of presentation that the active ingredient (morphine) has after one or more pharmaceutical operations carried out with the addition of suitable excipients or without the addition of excipients, in order to facilitate its usage and to achieve the desired therapeutic effect, with characteristics suitable for a certain administration route [Resolution RDC No. 133, of May 29, 2003] .
- presentation form refers to the indication of the form in which the pharmaceutical product is presented to the market, including the dosage, that is, the amount of active substance per volume unit, and the primary packing that is a container or any other packing form, which is in direct contact with the injectable solution.
- single dosage form refers to a presentation form containing a defined amount of the drug, with the intention of applying the total of such amount as a single dosage.
- a single dosage of the present invention is an amber glass ampoule with capacity for 1 mL, containing 0.1 mg/mL of morphine sulfate (expressed as pentahydrate) .
- the diluted morphine pharmaceutical composition of the present invention is prepared in an aqueous medium, sterilized by filtration through a 0.22 ⁇ m sterilizing membrane and bottled in amber glass ampoules or syringes for single use or in amber or protected with amber coating plastic bags, and sealed under nitrogen atmosphere.
- the production of the present invention composition is carried out in a sterile environment.
- the procedure for producing the present invention composition consists of dissolving the pharmaceutically acceptable morphine salt in a physiologically acceptable solvent, optionally adding a physiologically acceptable acid or buffer to adjust the pH at the desired interval, and filtering the resulting solution through a sterilizing filter.
- the pharmaceutical composition of morphine of the present invention provides to the health professionals a safe drug for epidural or intrathecal administration in adults and intravenous in children, available for immediate use, eliminating the existing inconvenience of using such administration route, considering there is no need for a previous preparation to use the drug.
- Example 1 For the stability evaluation, the composition of Example 1 was stored at a temperature around 30 °C (long duration) and 40 0 C (accelerated) .
- the analytical parameters evaluated were aspect, dosage and pH of the composition.
- the results presented in the table hereunder correspond to the partial results of the analysis.
- compositions and presentation form of the present invention would benefit patients to be submitted to medical procedures in gynecology and obstetrical specialty. In addition, dosages closer to the indications would be made available to pediatric patients.
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Abstract
The present invention refers to an analgesic composition in the form of an injectable solution, sterile and apyrogenic, which is constituted by a pharmaceutically acceptable morphine salt dissolved in a pharmaceutically acceptable solvent (carrier), wherein the pH of the resulting solution is from 2.5 to 6.5 and the morphine concentration is from about 0.025 to 0.195 mg/mL (expressed as the hydrated salt thereof). Such composition, packed in a sealed container is ready-to-use and suitable for epidural and intrathecal administration in adults and intravenous in children.
Description
"PHARMACEUTICAL COMPOSITION OF MORPHINE IN READY-TO-USE INJECTABLE SOLUTION FORM AND SINGLE DOSAGE FORM OF MORPHINE FOR EPIDURAL OR INTRATHECAL ADMINISTRATION".
The present invention describes morphine diluted pharmaceutical compositions, bottled in amber glass ampoules, vials or syringes for single doses or in plastic bags. More specifically, the present invention describes a morphine diluted pharmaceutical formulation, in ready-to-use form, appropriated for administration via epidural or intrathecal routes in adults, or via intravenous route in children, in pre- and post-surgical procedures delivering a sufficient and safe dosage of the drug.
Morphine is included in the pharmacological group of opioid analgesics, and placed among the most potent narcotic agents of clinical use, which produce depression of the Central Nervous System (CNS) . The analgesic and depressing effects of such drug occur through the interaction with CNS μ-opioid receptors, referred as responsible for the effects of analgesia, euphoria, potential of addiction and breathing depression, and kappa receptors, also of the CNS that mediates the spinal analgesia, myosis and sedation, altering responses to pain and eliminating anxiety and apprehension. This drug is mainly used for relief of moderately severe to severe pain (for example, cancer pain) , myocardial infarct associated pain, post-surgery pain and dyspnea associated to left ventricular acute insufficiency and lung edema, and suppression of severe cough and severe diarrhea (for example, the one caused by cholera) .
Morphine, CAS RN = 57-27-2, is identified by the chemical name (5-alpha, 6-alpha) -7, 8-Didehydro-4, 5-epoxy-17- methylmorphinan-3, 6-diol. Due to the low water solubility of its neutral form, morphine is usually employed in the form of morphine sulfate or morphine hydrochloride, which presents improved water solubility.
Pharmaceutical preparations of morphine sulfate are commercially available in the injection (0.2 mg/mL to 50 mg/mL) , capsule (15 and 30 mg) , tablet (10, 15 and 30 mg) , sustained release tablet (15, 30, 60, 100 and 200 mg) , oral solution (2 mg/mL to 20 mg/mL) and rectal suppositories (5, 10, 20 and 30 mg) forms.
The dosages used for the treatments involving morphine vary with the administration route, due to the differences in bioavailability: intravenous (100%), oral (33%), transmucosal (30-60%) and rectal (30-40%) . The usual dosage range is from 5 to 20 mg/70 Kg at every 4 hours, depending on pain severity. Dosages of 10 mg/70 Kg at every 4 hours via intramuscular route are used for moderate to severe pains. The oral dosage usually ranges from 8 to 20 mg, but under oral administration, morphine has substantially lower analgesic power (approximately 1/10 of the effect produced by subcutaneous injection) due to its fast degradation when passing through liver, immediately after its absorption. The intravenous administration route is primarily employed in severe post-surgery pain or in emergencies; in this case the dosage range may be comprised from 2 to 10 mg for the analgesic effect.
The epidural, intrathecal (or subarachnoid) administration or morphine infusion may be employed on patients that present refractory pain. For intrathecal administration, the usual dosage range is from 0.2 to 1 mg, which is able to provide satisfactory pain relief for up to 24 hours. One should not administrate more than 2 mg through this route, due to severe side effects, such as breathing depression that may occur.
Morphine may also be combined with other non-opioid analgesics or with psychotropic drugs.
Several experimental trials carried out in laboratory provided the basis for clinical use of opioids in man, with safety and efficacy in the control of acute and chronic pain. For example, Wang et al [Wang JK, Nauss LA, Thomas JE - Pain relief by intrathecally applied morphine in man. Anesthesiology, 1979; 50 : 149-151] demonstrated long lasting analgesia with morphine by subarachnoid via in man. Since then, opioids are frequently being employed by intrathecal route for relief of acute and chronic pain.
In order to investigate the efficacy of the analgesic technique and incidence of complications Gwirtz et al. [Gwirtz KH, Young JV, Byers RS, Alley C, Levin K, Walker SG, Stoelting RK, Anesth Analg. 1999 Mar; 88 (3) : 599-604] have prospectively evaluated patients that had received opioid via intrathecal route to control the post-surgery pain of urologic, orthopedic, vascular, thoracic and non-obstetrical gynecologic surgeries. They concluded that during a 7 years period, analgesia with intrathecal opioid was used to control post-surgical pain in approximately 6000 patients,
resulting in high levels of patients' satisfaction and low side effects and complications incidence.
Morphine is a hydrophilic opioid that promotes intense and long lasting analgesia. For being hydrophilic, its action duration is extended, however, this characteristic is also responsible for drug permanence in the liquor for a period longer than with a lipophilic opioid. Thus, a larger opioid diffusion occurs to the cranial region, which can provoke side effects such as itching, nausea, vomit and breathing depression. The presence of such side effects limits the use of morphine by spinal route.
In this way, many studies have been investigating the possibility of administration of a morphine dosage which produces analgesic effect without side effects, or that the side effects are reduced if compared to the effects caused by the dosages currently used. Generally, such studies have shown/elected the subarachnoid route with lower doses of morphine as a way to reduce the risks of dose-dependent side effects.
Small subarachnoid dosages of morphine are efficient for reducing the post-surgery pain of patients submitted to cesarean, with lower incidences of side effects. The morphine dosage recommended for administration in the subarachnoid space is 0.1 mg [Dahl JB, Jeppesen IS, Jorgensen H et al Anesthesiology, 1999; 91:1919-1927; Palmer CM, Emerson S, Volgoropolous D et al Anesthesiology, 1999; 90 : 437-444] , however, there are clinical works showing that morphine would achieve its maximum effect with dosages lower than 0.1 mg [Sibilla C, Albertazzi P, Zateli R et al, Int J Obstet Anaesth, 1994; 3:203-
207]. However, some authors found that 0.1 mg of morphine was efficient for blocking pain only when associated with other analgesics [Swart M, Swell J, Thomas D, Anaesthesia, 1997/52:364-381] .
It is believed that lower morphine dosages via subarachnoid route, associated with other analgesic drugs could be efficient in reducing post-surgery pain with lower incidence of side effects. For example, morphine, in the dosage of 0.025mg via subarachnoid route, associated with other non-steroidal anti-inflammatory drugs (diclofenac) , provided a good analgesia quality, with minimal side effects [Cardoso MMSC, Carvalho JCA, Amaro AR et al, Anesth Analg, 1998; 86:538-541] .
Babita et al. [BABITA G. RASHMI M, DEB K., Internat J Obstetr Anesth. 10:125-128. 2001] showed that combined epidural spinal anesthesia for cesareans of patients with left lung agenesis is safe and appropriate for such patients. The patients received low dosage of epidural morphine with local anesthetic and intramuscular diclofenac for post-surgery analgesia.
Ganem EM et al. [GANEM EM, MODOLO NSP, FERRARI F, CORDON FCO, KOGUTI ES, CASTIGLIA YMM., Rev Bras Anest 53 (4) : 431-439.2003] have evaluated the quality of post-surgery analgesia and the occurrence of side effects in patients submitted to cesareans, under subarachnoid anesthesia with hyperbaric bupivacaine and morphine in dosages of 0.05 mg and 0.1 mg, associated to ketoprofen via intravenous and oral route. In this study, the morphine dosages of 0.05 mg and 0.1 mg associated to ketoprofen were considered efficient for
blocking the pain during the first 12 hours of post-surgery and, after 24 hours of surgery, the pain was of mild intensity. What can be observed on the side effects of morphine is that, even with small dosages, some patients presented symptoms of itching, nausea and vomit episodes
(about 10 to 20%) . This is an important sign that such types of side effects are not dose-dependent. However, the effect of respiratory depression is not observed in any of the cases when morphine is used at this concentration range.
Hirahar JT et al. [HIRAHAR JT. BLIACHERIENE S, YAMAGUCHI ET, ROSA MCR, CARDOSO MMSC, Rev Bras Anest 53 (6) : 737-742. 2003], have demonstrated that the administration of diclofenac via muscular route or ketoprofen via intravenous route, when combined with low dosage of morphine via subarachnoid route, promotes similar quality post-surgery analgesia in cesareans.
The multimodal association for pain control has already been emphasized as a way to improve the efficacy of analgesia through drugs with different action mechanisms. The association of 0.1 mg or 0.05 rag of morphine with diclofenac or ketoprofen has been elected as a good option for treating post-cesarean pain, due to the fact that the drugs excretion in maternal milk in these dosages is safe for the neonate, allowing immediate suckling [CARDOSO MM - Letters to the Editor, Rev Bras Anest jul-ago 54 (4) : 621-622, 2004] .
The most important information obtained from several studies previously mentioned is that the dosages of morphine required to produce analgesia in peripheral tissue are
extremely small and therefore, in general, free from the known side effects produced by dosages sufficient for exerting influences on brain. In addition, the majority of the studies have been dedicated to the development of methods that allows the expansion of the use of morphine as analgesic, but the prior art lacks products that facilitate the application of the methodology.
Up to now there are no pharmaceutical formulations containing low morphine concentrations that allow the administration of about 0.05 to 0.1 mg of morphine via epidural or intrathecal (subarachnoid) route. In order to apply such methodology, the health professional needs to dilute from 10 to 20 times the 1 mg/mL commercial morphine formulation. This dilution step requires time and caution for its preparation in order to prevent dilution errors and solution contamination, which would endanger its therapeutic use. Or, the health professional needs, for example, to separate part of the volume of the 1 mg/mL commercially available morphine formulation, leaving a residual volume in the container that should be mandatory discarded.
The literature describes some propositions for obtainment of pharmaceutical compositions that limit or control the morphine dosage.
Patent US 5,589,480, filed on August 17, 1994, refers to the use of a diluted solution of analgesic opioid drugs, such as morphine, specifically morphine sulfate, approaching method and apparatus for the topic administration of such drugs, in sufficient concentration to produce analgesic effect in a located area, typically swollen, without opioid
drug migration into the blood circulation. Through this type of administration, the drug acts on opioid receptors found in peripheral tissues, preventing undesirable effects that occur through the activation of receptors located in the brain, mainly the addiction. A single dose is equivalent to 3 mg of morphine per 6 square inches of affected area.
Patent US 5,919,473, filed on May 12, 1997 refers to a drug release device for intradermal administration containing an analgesic agent, among them the morphine and a polymeric material. Such device releases the analgesic for at least 1 day through a surgical stitching and the amount of drug is insufficient to produce CNS mediated analgesia. The amount of morphine in one single dosage may range from 0.01 mg/4h/10cm to 8mg/4h/10cm of wound. This invention also describes a method for treatment of post-surgery pain associated to wounds or swollen/painful areas, by means of the device described above.
The international application WO 98/16197 refers to a medicinal paste containing an opioid analgesic (10-500mg), especially morphine, and a microfibrillar collagen (100- lOOOmg) , for use in a surgical procedure to reduce pain. The paste is directly administered in the epidural space and significantly improves the control of lumbar post-surgical pain. The paste may contain, in association with the analgesic agent, an anti-inflammatory, preferably a steroid. The examples of formulation for the favorite pastes of this invention use 3-5mg of Epimorph®.
Patent JP 6239746, filed on February 12, 1993, refers to a preparation of morphine sustained release, which
contains morphine microcapsules (≤ lOOμm) , formed from a morphine solution, a medium containing a contrast, an amino acid, an amide or a higher alcohol, in a sodium chloride solution for injection, artificial spinal fluid or local anesthetic. Such preparation is injected in the subarachnoid cavity or epidural space. The preparation is especially used for cancer pain relief providing efficient levels of morphine in the blood for about 100 days after an infusion.
The international application WO 03/035002, filed on October 24, 2002, also describes the administration of opioids via epidural route. This document refers to a formulation containing an opioid, such as morphine, in concentration lower than 2 mg, preferably 1 mg, in a drug- release controlling carrier. The carrier may be a gel, micro-particles or implant, preferably a gel, such as carbohydrate polymer gel ADCONΦ-L, which acts as a barrier for the development of epidural fibrosis, originating from lumbar procedures, besides controlling the drug release. The formulation of this invention has the purpose of pain treatment for a period of one or more days after spinal cord surgery and/or other structures associated with the Central Nervous System.
The international application WO 97/03652 refers to a sustained release formulation of an opioid therapeutic agent, such as morphine sulfate for epidural administration. The opioid, which is encapsulated within the non-concentric aqueous double-layers of multivesicular liposome is released for a long period of time when the liposomes are introduced
through epidural route, as a single dose for continued analgesia.
The application WO 04/091593 describes compositions containing a combination of an opioid antagonist and an opioid agonist for neuropathic pain relief. Among a list of preferred combinations are included naltrexone and morphine, nalmephene and morphine, naloxone and morphine. Naltrexone, nalmephene or naloxone amount ranges from 0.000001 mg to 1.0 mg, whereas morphine amount ranges from 0.1 mg to 300 mg. In the case of intravenous, intramuscular, subcutaneous, intrathecal, epidural, perineural and intradermal administration the active ingredients may be combined with a sterile aqueous solution.
Patent US 5,346,903 refers to a preparation for injection in aqueous suspension form containing a local anesthetic and/or water-insoluble narcotic analgesic (1 to 15% in weight, which is, from 10 to 150 mg/mL) suspended in an aqueous medium, with the suspension being stabilized by a non-ionic surfactant agent. A method for preparing the suspension and the use of this preparation in epidural, intrathecal, conduction and infiltration anesthesia is also described. The average particles diameter of the active agent is less than 20 μm. As an illustration of this invention, it is described that a stable suspension may be produced from 1 g of powder form morphine, having a particle size of 15 μm using 10 mL of a 0.9% NaCl solution containing 2.5 mg of polissorbate 80 (about 0.025% by weight). For stability of the suspension the pH is adjusted in the interval of 9-11.
The product Depodur® is a sterile multivesicular liposome suspension containing morphine sulfate in 0.9% NaCl solution for epidural administration. Each vial contains 10 mg/mL of morphine sulfate (expressed as pentahydrate) and the inactive ingredients include 1, 2-dioleoyl-sn-glycero-3- phosphocholine, cholesterol, 1, 2-dipalmitoyl-sn-glycero-3- phospho-rac (1-glycerol) , tricaprylin and triolein. Some patents related to this product are US 5,723,147, WO
98/33483 and WO 98/14171. Such product is not indicated for intrathecal, intravenous or intramuscular administration.
Patent US 5,723,147 refers to a multivesicular liposome containing a biologically active substance encapsulated in the presence of a hydrochloride that is used for modulating the release rate of the encapsulated active. This document describes a multivesicular liposome composition containing an active compound, such as morphine sulfate (expressed as pentahydrate) , an amphipathic lipid, a neutral lipid and hydrochloric acid.
Patent US 6,310,072 describes an analgesic composition containing a sub-analgesic dosage of an agonist opioid of μ- receptor, such as morphine or pharmaceutically acceptable salts thereof, and a sub-analgesic dosage of oxycodone which is an opioid agonist of kappa-receptor. The dosages of morphine and oxycodone are specified on account of the administration route, if the patient is an adult or a child, and if the dosage form is of immediate or sustained release. The lower morphine dosage range reported is from 0.05 to 0.25 mg per day, for intracerebral ventricular administration .
Patent literature reveals several approaches related to the use of morphine, but still there is a lack of simple, safe and efficient alternatives in the area of surgery and post-surgery pain treatment. The several proposals presented so far, do not describe ready-to-use compositions sufficiently diluted, appropriated for administration via epidural or intrathecal (subarachnoid) routes for postsurgical pain relief.
The objective of the present invention is to propose diluted presentations of morphine, appropriate for continuous, intravenous, intrathecal or epidural analgesia, or in analgesia controlled by the patient.
Morphine is usually administered in the form of morphine sulfate, although hydrochloride and tartarate salts thereof may also be used in similar doses.
The analgesic composition of the present invention is in the injectable solution form, apyrogenic and sterile, which is constituted of a pharmaceutically acceptable morphine salt dissolved in a pharmaceutically acceptable solvent (carrier) , being the pH of the resulting solution in the range of 2.5 to 6.5 and the morphine concentration is of about 0.0188 to 0.1466 mg/mL (expressed as free base). As the morphine dosages are usually expressed as salts thereof, the morphine concentration in the composition of the present invention is from 0.025 to 0.195 mg/mL (expressed as sulfate or hydrochloride hydrated salt thereof) .
In the composition of the present invention, morphine is used in the form of pharmaceutically acceptable salts thereof, selected from the group consisting of morphine
sulfate and morphine hydrochloride, either the anhydrous or the hydrated. The morphine concentration in the resulting solution ranges from 0.025 to 0.195 mg/mL. Preferably, the morphine concentration ranges from 0.05 to 0.1 mg/mL (expressed as sulfate or hydrochloride hydrated salt thereof) .
The solvent (carrier) of the composition of the present invention is selected from a group consisting of water for injection, physiological saline solution, artificial spinal fluid and local anesthetics solutions. The carrier is preferably 0.9% physiological solution, but other diluents may equally be applied in the preparation of the formulation like for example, water for injection, glucose or dextrose solution, artificial spinal fluid or local anesthetics solutions.
In order to be appropriate for epidural and intrathecal administration route, the pharmaceutical composition of the present invention is free of antioxidants, preservatives or other potentially neurotoxic additives.
According to the present invention, a pharmaceutical composition is presented containing morphine, in diluted aqueous solution and ready-to-use form, which enables the direct use of this drug, with no need of previous preparation.
The term )"diluted solution", as used herein, means that low dosages of morphine are administered to the patient, when compared with the dosages previously administered in solution or in a carrier that does not provide sustained release.
The presentation form of the present invention composition provides the appropriate pharmaceutical form for morphine administration and achievement of the desired therapeutic effect.
The term "pharmaceutical form", as used herein, refers to the final state of presentation that the active ingredient (morphine) has after one or more pharmaceutical operations carried out with the addition of suitable excipients or without the addition of excipients, in order to facilitate its usage and to achieve the desired therapeutic effect, with characteristics suitable for a certain administration route [Resolution RDC No. 133, of May 29, 2003] .
The term "presentation form", as used herein, refers to the indication of the form in which the pharmaceutical product is presented to the market, including the dosage, that is, the amount of active substance per volume unit, and the primary packing that is a container or any other packing form, which is in direct contact with the injectable solution.
The term "single dosage form", as used herein, refers to a presentation form containing a defined amount of the drug, with the intention of applying the total of such amount as a single dosage. As an illustration, a single dosage of the present invention is an amber glass ampoule with capacity for 1 mL, containing 0.1 mg/mL of morphine sulfate (expressed as pentahydrate) .
The diluted morphine pharmaceutical composition of the present invention is prepared in an aqueous medium,
sterilized by filtration through a 0.22 μm sterilizing membrane and bottled in amber glass ampoules or syringes for single use or in amber or protected with amber coating plastic bags, and sealed under nitrogen atmosphere.
The production of the present invention composition is carried out in a sterile environment. The procedure for producing the present invention composition consists of dissolving the pharmaceutically acceptable morphine salt in a physiologically acceptable solvent, optionally adding a physiologically acceptable acid or buffer to adjust the pH at the desired interval, and filtering the resulting solution through a sterilizing filter.
The pharmaceutical composition of morphine of the present invention provides to the health professionals a safe drug for epidural or intrathecal administration in adults and intravenous in children, available for immediate use, eliminating the existing inconvenience of using such administration route, considering there is no need for a previous preparation to use the drug.
The present invention is given hereunder, more detailed, in the form of illustrative examples, however not exhaustive, of the several possibilities herein comprised.
EXAMPLE 1
In a reactor with capacity for 5 L, equipped with stirring system, were added 4.5 L of water for injection, 45 g of sodium chloride, 0.9 mL of IM hydrochloric acid solution and 0.5 g of morphine sulfate pentahydrate
(equivalent to 0.376 g of morphine). The mixture was stirred until complete dissolution of the solids, maintaining a positive inert atmosphere (N2) . The pH of the mixture was adjusted in the range of 3.4-3.6 with HCl and filled with water for injection to its final volume of 5 L. The solution was filtered through a sterilizing membrane of 0.22 μ and bottled in 1 mL amber ampoules. Each ampoule contains 0.1 mg/mL of morphine sulfate pentahydrate.
EXAMPLE 2
In a reactor with capacity for 5 L, equipped with stirring system, were added 4.5 L of water for injection, 45 g of sodium chloride, 0.9 mL of IM hydrochloric acid solution and 0.25 g of morphine sulfate pentahydrate (equivalent to 0.188 g of morphine). The mixture was stirred until complete dissolution of the solids, maintaining a positive inert atmosphere (N2) « The pH of the mixture was adjusted in the range of 3.4-3.6 with HCl and filled with water for injection to its final volume of 5 L. The solution was filtered through a sterilizing membrane of 0.22 μ and bottled in 1 mL amber ampoules. Each ampoule contains 0.05 mg/mL of morphine sulfate pentahydrate.
For the stability evaluation, the composition of Example 1 was stored at a temperature around 30 °C (long duration) and 400C (accelerated) . The analytical parameters evaluated were aspect, dosage and pH of the composition. The results presented in the table hereunder correspond to the partial results of the analysis.
Despite the administration of low dosages of morphine, as well as its effects and the potential risks reduction are already described in the literature, there is not a commercially available product that fulfills the market necessity. This lack of prior art is overcome by the present invention, ready-to-use pharmaceutical presentation of diluted morphine, which consists in a simple, efficient and safe approach of morphine administration in pain treatment.
The pharmaceutical composition and presentation form of the present invention and, especially, in single dosage form, would benefit patients to be submitted to medical procedures in gynecology and obstetrical specialty. In addition, dosages closer to the indications would be made available to pediatric patients.
Claims
1. Analgesic composition in the form of an injectable, sterile and apyrogenic solution, characterized by the fact that the solution is in ready-to-use form and comprises a pharmaceutically acceptable morphine salt, selected from the group consisting of morphine sulfate and morphine hydrochloride, in its anhydrous or hydrated forms, dissolved in a pharmaceutically acceptable solvent, wherein the pH range of the resulting solution from 2.5 to 6.5 and the morphine concentration expressed as the hydrated salt thereof is from about 0.025 to 0.195 mg/mL.
2. Analgesic composition, according to claim 1, characterized by the fact that the solvent is selected from the group consisting of water for injection, physiological saline solution, glucose solution, dextrose solution, local anesthetics solution and artificial spinal fluid.
3. Analgesic composition, according to claim 1, characterized by the fact that the solvent is 0.9% sodium chloride solution.
4. Analgesic composition, according to claim 1, characterized by the fact that the ready-to-use solution comprises morphine sulfate pentahydrate, employed in concentrations ranging from 0.05 to 0.1 mg/mL.
5. Analgesic composition, according to claim 1, characterized by the fact that the ready-to-use solution comprises morphine hydrochloride trihydrate, employed in concentrations ranging from 0.05 to 0.1 mg/mL.
6. Analgesic composition, according to claim 1, characterized by the fact of being preservatives and/or conservatives free.
7. Analgesic composition, according to claim 1, characterized for being presented as a ready-to-use single dosage form, packed in a sealed container.
8. Analgesic composition, according to claim 7, characterized by the fact that the container is selected from the group constituted by amber glass ampoule or syringe.
9. Analgesic composition, according to claim 1, characterized for being presented packed in a ready-to- use amber, or protected by an amber coating, plastic bag in continuous analgesia or controlled by the patient.
10. Analgesic composition, according to claim 1, characterized for being suitable for intrathecal or epidural administration in adults and children, and intravenous administration in children.
11. Injectable form, characterized by comprising an amber, or protected with amber coat, plastic bag containing the analgesic composition of claim 1, for pediatric use.
12. Single dosage form, characterized by comprising an ampoule containing an analgesic composition of claim 1.
13. Single dosage form, characterized by comprising a syringe with rachidian anesthesia needle containing the analgesic composition of claim 1.
14. Single dosage form, characterized by comprising an ampoule containing from 0.05 to 0.1 mg/itιL of a pharmaceutically acceptable morphine salt selected from the group consisting of morphine sulfate and morphine hydrochloride, dissolved in a pharmaceutically acceptable solvent, wherein the pH of the resulting solution is from 2.5 to 6.5 and the concentration of morphine expressed as the hydrated salt thereof.
15. Single dosage form, according to claim 14, characterized by the fact that the solvent is selected from the group consisting of water for injection, physiological saline solution, glucose solution, dextrose solution, local anesthetics solution and artificial spinal fluid.
16. Single dosage form, according to claim 14, characterized by the fact that the solvent is 0.9% sodium chloride solution.
17. Single dosage form, according to claim 14, characterized by the fact of being preservatives and/or conservatives free.
18. Single dosage form, according to claim 14, characterized by the fact of being in ready-to-use form.
19. Single dosage form, according to claim 14, characterized by the fact that the ampoule is made of amber glass with capacity for 1 mL or 2 mL of injectable solution.
20. Single dosage form, characterized by comprising a syringe with rachidian anesthesia needle containing from 0.05 to 0.1 mg/mL of a pharmaceutically acceptable morphine salt selected from the group consisting of morphine sulfate and morphine hydrochloride, dissolved in a pharmaceutically acceptable solvent, wherein the pH of the resulting solution is from 2.5 to 6.5 and the morphine concentration expressed as the hydrated salt thereof.
21. Single dosage form, according to claim 20, characterized by the fact that the solvent is selected from the group consisting of water for injection, physiological saline solution, glucose solution, dextrose solution, local anesthetics solution and artificial spinal fluid.
22. Single dosage form, according to claim 20, characterized by the fact that the solvent is 0.9% sodium chloride solution.
23. Single dosage form, according to claim 20, characterized by the fact of being preservatives and/or conservatives free.
24. Single dosage form, according to claim 20, characterized by the fact of being in ready-to-use form.
25. Single dosage form, according to claim 20, characterized by the fact that the syringe with rachidian anesthesia needle is made of amber glass with capacity for 1 itiL or 2 mL of injectable solution.
26. Single dosage form, characterized by comprising an ampoule containing 0.1 mg/mL of morphine sulfate pentahydrate dissolved in a 0.9% sodium chloride solution and preservatives, conservatives or other additives free.
27. Single dosage form, characterized by comprising an ampoule containing 0.05 mg/mL of morphine sulfate pentahydrate dissolved in a 0.9% sodium chloride solution and preservatives and/or conservatives free.
28. Single dosage form, characterized by comprising an ampoule containing 0.1 mg/mL of morphine hydrochloride trihydrate dissolved in a 0.9% sodium chloride solution and preservatives, conservatives or other additives free.
29. Single dosage form, characterized by comprising an ampoule containing 0.05 mg/mL of morphine hydrochloride trihydrated dissolved in a 0.9% sodium chloride solution and preservatives and/or conservatives free.
30. Single dosage form, characterized by comprising a syringe with rachidian anesthesia needle, containing 0.1 mg/mL of morphine sulfate pentahydrate dissolved in a 0.9% sodium chloride solution and preservatives and/or conservatives free.
31. Single dosage form, characterized by comprising a syringe with rachidian anesthesia needle, containing
0.05 mg/mL of morphine sulfate pentahydrate, dissolved in a 0.9% sodium chloride solution and preservatives and/or conservatives free.
32. Single dosage form, characterized by comprising a syringe with rachidian anesthesia needle containing 0.1 mg/mL of morphine hydrochloride trihydrate, dissolved in a 0.9% sodium chloride solution and preservatives and/or conservatives free.
33. Single dosage form, characterized by comprising a syringe with rachidian anesthesia needle, containing
0.05 mg/πιL of morphine chloridrate thihydrate , dissolved in a 0.9% sodium chloride solution and preservatives and/or conservatives free.
Applications Claiming Priority (2)
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BRPI0503734-4 | 2005-08-23 | ||
BRPI0503734 BRPI0503734A (en) | 2005-08-23 | 2005-08-23 | pharmaceutical composition in ready-to-use morphine solution for injection and unit dosage form of morphine for epidural or intrathecal administration |
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WO2007022609A1 true WO2007022609A1 (en) | 2007-03-01 |
WO2007022609B1 WO2007022609B1 (en) | 2007-04-12 |
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PCT/BR2006/000168 WO2007022609A1 (en) | 2005-08-23 | 2006-08-18 | Pharmaceutical composition of morphine in ready-to-use injectable solution form and single dosage form of morphine for epidural or intrathecal administration |
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WO2014140899A3 (en) * | 2013-03-15 | 2015-01-29 | Johnson Matthey Public Limited Company | Morphine sulfate methanolic solvate, processes for making same and related compositions and methods for treating pain |
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US20140005219A1 (en) * | 2012-03-07 | 2014-01-02 | Mallinckrodt Llc | Intrathecal hydromorphone solutions having improved stability |
US10905685B2 (en) * | 2012-03-07 | 2021-02-02 | Piramal Critical Care, Inc. | Intrathecal hydromorphone solutions having improved stability |
JP2016512210A (en) * | 2013-03-14 | 2016-04-25 | ベクトン ディッキンソン フランス エス.エー.エス. | Injectable morphine preparation |
US9545473B2 (en) | 2013-03-14 | 2017-01-17 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US9072781B2 (en) | 2013-03-14 | 2015-07-07 | Becton, Dickinson France S.A.S. | Morphine formulations |
US11214426B2 (en) | 2013-03-14 | 2022-01-04 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US9192608B2 (en) | 2013-03-14 | 2015-11-24 | Becton Dickinson France S.A.S. | Morphine formulations |
US9248229B2 (en) | 2013-03-14 | 2016-02-02 | Becton, Dickinson France S.A.S. | Packaging system for oxygen-sensitive drugs |
WO2014140095A1 (en) * | 2013-03-14 | 2014-09-18 | Becton Dickinson France S.A.S. | Injectable morphine formulations |
CN104042565A (en) * | 2013-03-14 | 2014-09-17 | 贝克顿狄金森法国公司 | Morphine Formulations, Kits Comprising The Morphine Formulations And Use Thereof |
EP3143988A1 (en) * | 2013-03-14 | 2017-03-22 | Fresenius Kabi Deutschland GmbH | Injectable morphine formulations |
CN109125254A (en) * | 2013-03-14 | 2019-01-04 | 费森尤斯卡比德国有限公司 | Morphine composite, the kit comprising the morphine composite and its purposes |
US10213424B2 (en) | 2013-03-14 | 2019-02-26 | Fresenius Kabi Deutschland Gmbh | Morphine formulations |
US10214338B2 (en) | 2013-03-14 | 2019-02-26 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US10781027B2 (en) | 2013-03-14 | 2020-09-22 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
WO2014140899A3 (en) * | 2013-03-15 | 2015-01-29 | Johnson Matthey Public Limited Company | Morphine sulfate methanolic solvate, processes for making same and related compositions and methods for treating pain |
US9127008B2 (en) | 2013-03-15 | 2015-09-08 | Johnson Matthey Public Limited Company | Morphine sulfate methanolic solvate, processes for making same and related compositions and methods for treating pain |
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BRPI0503734A (en) | 2007-04-27 |
WO2007022609B1 (en) | 2007-04-12 |
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