Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-19
2002-05-14
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S044000
Reexamination Certificate
active
06387917
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to new salts of opioid analgesics and more particularly to a new salt of morphine, which can be used in the treatment of pain following parenteral or non-parenteral administration.
Morphine is an opioid analgesic that is widely used to relieve severe pain, although it is also used to a lesser extent for its cough suppressant and anti-diarrheal properties. It was first isolated from an opium extract in the early 1800's but is still used as the gold standard with which new drugs with opioid activity are compared. The drug is basic in nature, the pKa of the tertiary amine is 7.93 (
Therapeutic Drugs
, 2d Ed, Dollery (ed.), Churchill Livingstone, Edinburgh (1999)). Salts of morphine, such as the hydrochloride and, more usually, the sulphate, are available commercially. The drug can be administered by injection (intravenous, intramuscular, epidural, intra-articular, intrathecal) or by oral and rectal routes.
More recently, the delivery of morphine via the nasal route in the form of a nasal spray or gel has been described (International Patent Application publication WO-82/03768). This route affords rapid onset of action and convenience to patients and/or the care-giver. Intranasal morphine has been found to be especially useful in the treatment of breakthrough pain and in the treatment of post-surgical pain.
In some clinical situations it is necessary to give high doses of morphine when a patient has become tolerant to the drug. For example, in the treatment of breakthrough pain a dose of 10-20 mg by injection or nasal spray may be effective, but in some patients much larger doses may be required.
This need for higher doses can present problems in the formulation of a delivery system for nasal administration. The limited solubility of the chosen salt form in the volume that can be administered effectively to the nose (150 &mgr;l maximum per nostril) can provide a serious limitation. The solubilities of known salts of morphine in water are listed in the
Merck Inclex
11th ed., Merck and Co (1989), as shown in Table 1 below.
TABLE 1
Solubility of morphine salts in water
Solubility
Salt form
(One gram dissolves in x parts of water)
Hydrochloride
17.5
Hydrobromide
25
Sulphate
15.5
Nitrate
1.5
Lactate
10
Acetate
2.25
Tartrate
11
Valerate
5
Monobasic phosphate
5 (U.S. Pat. 2,665,227)
Based on these solubility data, the maximum concentration of morphine hydrochloride or morphine sulphate (the most commonly used salts) as a simple aqueous solution is approximately 60 mg/ml. This would enable nasal dosing of a maximum of around 20 mg morphine as a single dose (based on dosing 0.15 ml of liquid into each nostril).
When developing novel solution formulations of morphine containing high concentrations of morphine, we have found that the salts described in the prior art are unsuitable, because of an inherently low solubility in water and/or instability at low temperatures and/or incompatibility with formulation additives. Such formulation additives include chitosan as an absorption promoter. Instability can be manifested by the formation of a precipitate or crystals of the drug. This phase separation is enhanced at low temperatures, such as found under refrigeration.
Injectable solutions containing high concentrations of morphine have been described in Japanese published patent application (Kokai) JP
09-208465
. Benzoate and/or salicylate salts were employed together with the hydrochloride salt of morphine. An injectable solution (2 ml) was formulated containing 200 mg morphine hydrochloride and 200 mg sodium benzoate.
U.S. Pat. No. 5,607,940 and European published patent application EP-A-0 623 345 have described a formulation of morphine for use by electromotive administration comprising morphine citrate salts.
International Patent Application PCT/US82/00546 has described intranasal formulations for opioid drugs. Any pharmaceutically acceptable form of morphine or its phenolic analogues could be used, e.g., the free base or a pharmaceutically acceptable acid addition salt thereof. The listed salts include hydrochloride, sulphate, tartrate, hydrobromide and lactate.
SUMMARY OF THE INVENTION
We have explored the use of alternative salts of opioid analgesics, such as morphine, suitable for the preparation of physically stable aqueous solutions. Surprisingly, we have found the methane sulphonate salt to be a suitable salt. This salt form is commonly termed “mesylate” or “mesilate”. According to one aspect of the present invention there is provided a methane sulphonate salt of morphine. There was no suggestion in the above-described prior art to use the methane sulphonate salt of morphine, and no suggestion that the methane sulphonate salt could be used for the improved solubility of any of the listed opioid drugs, and certainly no suggestion that the methane sulphonate salt of morphine could be advantageous.
The methane sulphonate salts of morphine and other opioid analgesics can provide physically stable aqueous solutions of the drug for parenteral or non-parenteral administration. By parenteral, we mean injection via intravenous, intramuscular, sub-cutaneous, intrathecal, epidural, intra-arterial or intra-articular routes. By non-parenteral, we mean administration either via mucosal surfaces in the nose, lung, buccal cavity, gastrointestinal tract (including the rectum), vagina, or eye or via the dermal layer of the skin (“transdermal”). For transdermal administration, the solution could be especially useful when employing electlically-enhanced delivery (iontophoresis) or ultrasound (sonophoresis).
According to a further aspect of the present invention, there is provided a composition adapted for nasal delivery comprising a methane sulphonate salt of an opioid analgesic, especially morphine. The nasally deliverable composition may form a gel once applied to the nose.
Preferred compositions for nasal delivery are solutions, particularly aqueous solutions, and more particularly aqueous solutions in which the methane sulphonate salt of the opioid analgesic is combined with chitosan or a salt or derivative thereof (hereinafter referred to collectively as “a chitosan compound”) to provide an increased absorption of the drug.
The present invention also provides a nasal drug delivery device, which contains as a drug a methane sulphonate salt of an opioid analgesic.
DETAILED DESCRIPTION OF THE INVENTION
The methane sulphonate salt can be prepared by mixing the opioid in base form with an equivalent of methane sulphonic acid and then recovering the product. When morphine base is used, the salt is recovered as a fine white odorless powder or as fine white odorless crystals.
Alternatively and preferably, the salt can be formed in situ by neutralising the opioid with methane sulphonic acid and then using the solution so prepared for medicinal use.
Methane sulphonic acid (CH
4
O
3
S) can be sourced commercially.
While the examples described below are directed to morphine salts, it will be understood by one of ordinary skill in the art based on the present disclosure, that salts of other opioid analgesic drugs could be similarly prepared. By opioid analgesic drugs we include, inter alia, diamorphine, fentanyl, tramadol, hydromorphone, hydrocodeine, codeine, oxycodone, oxymorphonc, buprenorphine, meperidine, pentazocine.
Generally, an aqueous pharmaceutical composition, e.g., for nasal administration, can be prepared as follows:
The selected amount of opioid in base form is mixed with an equimolar amount of methane sulphonic acid solution of appropriate molarity (for example 2M). By base form, we mean the drug in the non-salt form. If a chitosan compound is to be added to promote transmucosal absorption from the nasal cavity, then an appropriate amount, as a powder or an aqueous solution, is added to make the final concentration of the chitosan compound in the range of about 5-10 mg/ml. The formulation is adjusted to the desired pH (generally in the range about pH 4-7) by adding additional methane sulphonic acid solution or an alkali (
Illum Lisbeth
Lafferty Ian
Smith Alan
Watts Peter
Akin Gump Strauss Hauer & Feld L.L.P.
Aulakh Charanjit S.
West Pharmaceutical Services Drug Delivery & Clinical Research C
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