WO2000076477A1

WO2000076477A1 - Methods and compositions for treating breakthrough pain

Info

Publication number: WO2000076477A1
Application number: PCT/US2000/014663
Authority: WO
Inventors: Charanjit R. Behl; Vincent D. Romeo
Original assignee: Nastech Pharmaceutical Co., Inc.
Priority date: 1999-06-16
Filing date: 2000-05-26
Publication date: 2000-12-21
Also published as: AU5169200A

Abstract

The invention relates to methods and compositions for treating breakthrough pain in a mammal which includes nasally administering a therapeutically effective amount of an analgesic to the mammal to alleviate the breakthrough pain.

Description

METHODS AND COMPOSITIONS FOR TREATING BREAKTHROUGH PAIN

FIELD OF THE INVENTION The present invention relates to methods and compositions for treating breakthrough pain which includes nasally administering a therapeutically effective amount of an analgesic to alleviate the breakthrough pain.

BACKGROUND OF THE INVENTION

Breakthrough pain refers generally to a transitory exacerbation of pain that occurs in conjunction with a background or baseline pain. Such background pain is stable and well-controlled with the use of opioid and non-opioid analgesics.

Typically, breakthrough pain involves a transient increase in pain of moderate to severe intensity. Breakthrough pain is generally self-limiting, with a medium duration of approximately thirty minutes. However, it can be excruciating, even tortuous, during its brief duration, often escalating in pain intensity rapidly within three minutes. See for example, Portenoy et al., Breakthrough Pain: Definition, Prevalence and Characteristics, Pain, Elsevier Science Publishers BN. 41, 273-281 (1990) and J.F. Cleary, Pharmacokinetic and Pharmacodynamic Issues in the Treatment of Breakthrough Pain, Seminars in Oncology, 24:16, S16-113-S16-19 (1997).

Accordingly, breakthrough pain can be distinguished from chronic pain and acute pain. Chronic pain usually has slow onset and long duration. For example, chronic pain can last for days or even longer. Acute pain usually has short onset and short duration. Typically, acute pain occurs in the absence of analgesic therapy. By contrast, breakthrough pain occurs where the mammal is well-controlled on analgesic therapy. For example, breakthrough pain is often seen in cancer patients receiving chronic opioid therapy. Treating breakthrough pain is complex and frequently unsuccessful. The first line of treatment usually involves administration of an oral immediate release opioid or non-opioid analgesics. Some examples of non-opioid analgesics include acetaminophen, ibuprofen, aspirin and indomethacin. Examples of opioid analgesics include morphine, codeine, levorphanol, hydromorphone, oxymorphone, hydrocodone, oxycodone, and methadone.

Oral immediate release preparations are inadequate for treating breakthrough pain because they need to be absorbed from the gastro-intestinal tract, which takes approximately forty-five minutes after administration. This delay in absorption is typically longer than the episode of breakthrough pain. For example, immediate release oral morphine sulfate solution, i.e. Roxanol ®, results in a peak plasma level at approximately thirty to fifty-five minutes after oral administration which is often inadequate for treatment of breakthrough pain.

Ideally, the breakthrough pain analgesic should be absorbed quickly and produce a rapid onset of analgesia with minimal side effects. Intravenous intramuscular and subcutaneous injections of analgesics, have been investigated for treatment of breakthrough pain. The intravenous route provides minimal delays in absorption, with peak plasma levels almost instantaneously upon administration. For example, an intravenous infusion of morphine sulfate provides rapid peak plasma concentrations of morphine and rapid pain relief. However, the intravenous route is invasive, inconvenient, expensive, elicits fear and requires technical equipment and expertise in administering the drug.

Another route of administration for analgesics that has been investigated is the sublingual route. The sublingual tissue is highly vascularized and provides easy access to the bloodstream. However, some analgesics such as morphine sulfate have inadequate solubility in water and low permeability resulting in slow and low peak plasma concentration. Therefore, rapid relief of pain is not provided by this route. The intranasal route of delivery has been investigated for administration of analgesics. This route provides rapid onset and high peak plasma concentrations of analgesics with few side effects. For example, intranasal delivery of morphine is disclosed in U.S. Patent No. 5,629,011 to Ilium and U.S. Patent No. 4,464,378 to Hussain for the treatment of chronic and acute pain. The entire disclosure of U.S.

Patent No. 5,629,011 and U.S. Patent No. 4,464,378 is herein incorporated by reference. While these references discuss the benefits of intranasal delivery of morphine, there is no consideration of using this route for the treatment of breakthrough pain.

Based on the foregoing, there is a need for more effective methods and compositions for treating breakthrough pain in a mammal. The methods and compositions include nasally administering therapeutically effective amounts of an analgesic to the mammal to alleviate the breakthrough pain.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method for treating breakthrough pain in a mammal comprising nasally administering a therapeutically effective amount of an analgesic to the mammal to alleviate the breakthrough pain.

In another embodiment, the present invention includes a pharmaceutical composition for treating breakthrough pain in a mammal comprising a therapeutically effective amount of an analgesic in combination with a nasal delivery system.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods and compositions for treating breakthrough pain in a mammal by nasally administering to the mammal a therapeutically effective amount of an analgesic to alleviate or relieve breakthrough pain. As used herein, breakthrough pain is a transitory exacerbation of pain that occurs in conjunction with a background or baseline pain. Such background pain is stable and well-controlled with the use of opioid and non-opioid analgesics. Typically, breakthrough pain involves a transient increase in pain of moderate to severe intensity. Breakthrough pain is generally self-limiting, with a medium duration of approximately thirty minutes. However, it can be excruciating, even tortuous, during its brief duration, often escalating in pain intensity rapidly within three minutes.

Breakthrough pain can be distinguished from chronic pain and acute pain. Chronic pain usually has slow onset and long duration. For example, chronic pain can last for days or even longer. Acute pain usually has short onset and short duration.

Typically, acute pain occurs in the absence of analgesic therapy.

Analgesics

For the purposes of the present invention, analgesics can be divided into two categories, opioid and non-opioid. Non-opioid analgesics include acetaminophen, ibuprofen, aspirin, diflunisal, etodolac, fenoprofen, flurbiprofen, ketorolac, ketoprofen, meclofenamate, mefenamic acid, naproxen, oxaprozin, piroxicam, sulnidac, tolmetin, indomethacin and combinations thereof. Opioid analgesics include morphine, codeine, meperidine, alfentanil, fentanyl, sufentanil, propoxyphene, levorphanol, hydromorphone, oxymorphone, hydrocodone, oxycodone, methadone and combinations thereof.

Breakthrough pain is often associated with painful conditions such as that resulting after surgery, labor and child birth. Breakthrough pain is also associated with diseases such as arthritis, osteoarthritis, migraines, diabetes, cancer, osteoporosis, acute inflammation, chronic inflammation and can be pain of unknown origin. In one preferred embodiment, the morphine derivative is administered intranasally to alleviate breakthrough pain associated with cancer. For purposes of the present invention, morphine derivatives include morphine or (-)7,8-didehydro-4,5α-epoxy-17-methylmoφhinan-3,6c--diol, oxymorphone or (-)4,5α-Epoxy-3,14-dihyroxy-17-methylmorphinan-6-one, hydromorphone or (-)- 4,5α-epoxy-3-hydroxy-l 7-methylmorphinan-6-one, levorphanol (-)-17- methylmorphinan-3-ol, nalbuphine or (-)-17-(cyclobutylmethyl)-4,5α- epoxymorphinan-3,5α,14-triol, nalmefene or 6-desoxo-6-methylene-naltrexone, butorphanol or (-)-17-(cyclo-butylmethyl)-morphinan-3, 14-diol, buprenoφhine or (-)- 17-(cyclopropylmethyl)-α-( 1 , 1 -dimethylethyl)-4,5-epoxy- 18,19-dihydro-3- hydroxy-6-methoxy-o--methyl-6, 14-ethenomoφhinan-7-me thanol, codeine, hydrocodone, oxycodone, butoφhanol, methadone, meperidine, propoxyphene, pentazocine, and pharmaceutically acceptable salts thereof.

The present invention includes pharmaceutically acceptable salts of the analgesics. Some examples of pharmaceutically acceptable salts include those salt- forming acids and bases which do not substantially increase the toxicity of the compound. Some examples of suitable salts include salts of alkali metals such as magnesium, potassium and ammonium. Salts of mineral acids include hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, succinic, arylsulfonic, e.g. p-toluenesulfonic acids, and the like.

Particular examples of preferred moφhine derivatives of the present invention include moφhine sulfate, moφhine hydrochloride, moφhine tartrate, moφhine lactate, moφhine-6-sulfate, moφhine-3-sulfate, moφhine-6-glucuronide, moφhine- 3-glucuronide and combinations thereof.

The opioid or non-opioid analgesics useful in conjunction with nasal administration in accordance with the present invention are available commercially from various manufacturers and can be made by procedures well known in the art. For example, moφhine sulfate is available from Abbott Pharmaceuticals Inc., USA and can be made as described in Remington's Pharmaceutical Science, 18th Edition (1990), which is hereby incoφorated by reference.

Therapeutically Effective Amounts As used herein, a therapeutically effective amount is that amount effective to achieve the relief or palliation of breakthrough pain. Preferably, the analgesic is administered in an amount that limits the most common side effects such as respiratory depression, constipation and lethargy.

The minimal dosage of the analgesic is the lowest dosage which alleviates the breakthrough pain. For example, a moφhine derivative can be administered at a minimal dosage of preferably at least about 0.01 mg/kg to about 4 mg/kg of body weight, more preferably at least about 1 mg/kg to about 4 mg/kg of body weight, and most preferably at least about 2 mg/kg to about 4 mg/kg of body weight.

Maximal dosage for a mammal is the highest dosage which does not cause undesirable or intolerable side effects such as respiratory depression. In any event, the practitioner is guided by skill and knowledge in the field, and the present invention includes without limitation dosages which are effective to achieve the described effect.

Once the dosage range is established, a further advantage of the invention is that the mammal can self-administer the analgesic on an as-needed basis to alleviate the breakthrough pain. Thus, the frequency of administration is under control of the mammal. For example, the moφhine derivative can be administered every fifteen minutes to one hour or as needed until the breakthrough pain is alleviated in the mammal. Mammals include, for example, humans, as well as pet animals such as dogs and cats, laboratory animals, such as rats and mice, and farm animals, such as horses and cows.

Nasal Administration The present invention includes nasally administering to the mammal a therapeutically effective amount of an analgesic to alleviate or relieve breakthrough pain.

As used herein, nasally administering or nasal administration includes administering the analgesic to the mucous membranes of the nasal passage or nasal cavity of the mammal. In one embodiment, the present invention provides a pharmaceutical composition for treating breakthrough pain in a mammal comprising a therapeutically effective amount of an analgesic in combination with a nasal delivery system.

As used herein, pharmaceutical compositions include a therapeutically effective amount of the analgesic as discussed above. Such compositions can be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. The administration of the composition may also take place using a nasal tampon or nasal sponge containing the present composition.

The nasal composition may include powder formulations. Such powder formulations have the advantage that no preservatives are necessary. Preservatives are known to decrease the ciliary movement, which may be harmful in chronic nasal medication (Hermens AJ.J. and Merkus F.W.H.M., Pharm. Res. 1987; 4: 445-449).

Nasal powder compositions can be made by mixing the analgesic and an excipient, both possessing the desired particle size. Other methods to make a suitable powder formulation can be selected. First, a solution of the analgesic is made, followed by precipitation, filtration and pulverization. It is also possible to remove the solvent by freeze drying, followed by pulverization of the powder in the desired particle size by using conventional techniques, known from the pharmaceutical literature. Powders can be administered using a nasal insufflator or other suitable device.

Powders may also be administered in such a manner that they are placed in a capsule. The capsule is set in an inhalation or insufflation device. A needle is penetrated through the capsule to make pores at the top and the bottom of the capsule and air is sent to blow out the powder particles. Powder formulation can also be administered in a jet-spray of an inert gas or suspended in liquid organic fluids.

Analgesics of the present invention can also be brought into a viscous basis, using systems, conventionally used, for example methylcellulose and derivatives thereof and vinyl polymers (polyvinylpyrrolidone). In the present compositions, many other excipients, known from the pharmaceutical arts, can be added, such as preservatives, surfactants, co-solvents, adhesives, antioxidants, buffers, viscosity enhancing agents and agents to adjust osmolarity.

Preferably, the analgesic is combined with a suitable nasal delivery system for absoφtion across the nasal mucosa of a mammal. The nasal delivery system includes a pharmaceutically acceptable buffer, a thickening agent, a humectant and a surfactant and other excipients as discussed above. Such nasal delivery system can take various forms including, for example, aqueous and non-aqueous systems.

Aqueous systems, include for example, aqueous gels, aqueous suspensions, aqueous solutions, aqueous liposomes, aqueous emulsions, aqueous microemulsions. Non aqueous systems include, for example, non-aqueous gels, non-aqueous suspensions, non-aqueous solutions, non-aqueous liposomes, non-aqueous emulsions and non-aqueous microemulsions. The present delivery systems also include all types of particulate formulations, including for example, simple powders mixtures as set forth above, powder microspheres (coated and uncoated), ribosomes and mixtures thereof.

The various forms of the delivery system set forth above can include a buffer, a pharmaceutically acceptable thickening agent, humectant and surfactant. Buffers that are suitable for use in the present invention include, for example, acetate, citrate, prolamine, carbonate and phosphate buffers and combinations thereof. With respect to the non-aqueous and powder formulations set forth above, suitable forms of buffering agents can be selected.

The viscosity of the compositions of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent. Thickening agents that can be used in accordance with the present invention include for example, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, chitosans and combinations thereof. The concentration of the thickening agent will depend upon the agent selected and the viscosity desired. Such agents will also be used in the particulate formulations of the present invention.

In the present invention other optional ingredients may also be incoφorated into the nasal delivery system provided they do not interfere with the action of the analgesic or significantly decrease the absoφtion of the analgesic across the nasal mucosa. Such ingredients can include, for example, pharmaceutically acceptable excipients and preservatives. The excipients that can be used in accordance with the present invention include, for example, bio-adhesives and/or swelling/thickening agents.

To extend shelf life, preservatives can be added to the present compositions.

Suitable preservatives that can be used with the present compositions include, for example, benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium, with benzalkonium chloride being preferred. Typically, the preservative will be present in the present compositions in a concentration of up to about 2% by weight of the total composition. The exact concentration of the preservative, however, will vary depending upon the intended use and can be easily ascertained by one skilled in the art.

The present invention is based on the suφrising and unexpected discovery that nasal administration of analgesics can alleviate symptoms of breakthrough pain. The peak onset of intranasal moφhine sulfate can be therapeutically effective for treatment of breakthrough pain.

EXAMPLE 1 Intranasal Morphine Composition

A preferred pharmaceutical composition is prepared from material that is readily available in the art from various manufacturers. The formulation is mixed at room temperature and at one atmosphere of pressure as described below. This formulation can be used to treat breakthrough pain.

Formulation

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating breakthrough pain in a mammal comprising nasally administering a therapeutically effective amount of an analgesic to the mammal to alleviate the breakthrough pain.

2. A method according to claim 1, wherein the analgesic is a moφhine derivative.

3. A method according to claim 2, wherein the moφhine derivative is moφhine sulfate.

4. A method according to claim 1 , wherein the breakthrough pain is associated with surgery, medical procedures, arthritis, osteoarthritis, diabetes, cancer, migraines, osteoporosis, acute inflammation, chronic inflammation, labor, child birth and pain of unknown origin.

5. A method according to claim 1 , wherein the breakthrough pain is cancer breakthrough pain.

6. A method according to claim 2, wherein the therapeutically effective amount of the moφhine derivative is from about O.Olmg to about 4mg/kg of body weight.

7. A method according to claim 2, wherein the therapeutically effective amount of the moφhine derivative is from about lmg to about 4mg/kg of body weight.

8. A method according to claim 2, comprising administering the moφhine derivative every fifteen minutes to one hour or as needed.

9. A method according to claim 2, wherein the mammal can self- administer the moφhine derivative to alleviate the breakthrough pain.

10. A pharmaceutical composition for treating breakthrough pain in a mammal comprising a therapeutically effective amount of an analgesic in combination with a nasal delivery system.

11. A pharmaceutical composition according to claim 10, wherein the analgesic is a moφhine derivative.

12. A pharmaceutical composition according to claim 11 , wherein the moφhine derivative is moφhine sulfate.

13. A pharmaceutical composition according to claim 10, wherein the breakthrough pain is associated with surgery, medical procedures, arthritis, osteoarthritis, diabetes, cancer, migraines, osteoporosis, acute inflammation, chronic inflammation, labor, child birth and pain of unknown origin.

14. A pharmaceutical composition according to claim 10, wherein the breakthrough pain is cancer breakthrough pain.

15. A pharmaceutical composition according to claim 11 , wherein the therapeutically effective amount of the moφhine derivative is from about O.Olmg to about 4mg/kg of body weight.

16. A pharmaceutical composition according to claim 11 , wherein the therapeutically effective amount of the moφhine derivative is from about lmg to about 4mg/kg of body weight.

17. A pharmaceutical composition according to claim 11, comprising administering the moφhine derivative every fifteen minutes to one hour or as needed.

18. A pharmaceutical composition according to claim 11 , wherein the mammal can self-administer the moφhine derivative to alleviate the breakthrough pain.

19. A pharmaceutical composition of according to claim 12, wherein moφhine sulfate is dispersed in an aqueous, non-aqueous and powder formulation.

20. A pharmaceutical composition of according to claim 12, wherein moφhine sulfate is dispersed in suspensions, powders, gels, ointments and creams.