Sublingual oral dosage form

Details Sublingual oral dosage form Sublingual oral dosage form

2000-09-08

2003-06-03

Hartley, Michael G. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C514S282000, C229S206000

Reexamination Certificate

active

06572891

ABSTRACT:

This invention relates to a pharmaceutical oral dosage, particularly to a formulation for administration of a salt of morphine or a morphine derivative. In particular the present invention is concerned with a formulation containing morphine sulphate.
Morphine is used for control of moderate to severe pain and morphine salts have historically been administered by different routes. Solutions or delay release oral formulations have been used for treatment of chronic pain, for example in cancer patients. However adverse effects include gastrointestinal disturbances, constipation and difficulty in establishing the correct dosage. Metabolism of morphine by the liver makes higher doses necessary. Controlled release formulations are difficult to administer to patients suffering from swallowing disorders. Poor absorption from controlled release buccal tablets has also been reported.
Formulations containing morphine are well documented in the prior art.
U.S. Pat. No. 6,077,533 discloses an oral dosage form of morphine which is formulated by powder layering an homogeneous mixture of morphine sulphate and hydrous lactose impalpable on to inert beads to obtain a multi-particular product. The advantage of this product is that it provides a high-load immediate release multi-particulate formulation of morphine giving effective blood plasma levels for up to 4 hours, which can be formulated for extended release to provide effective blood plasma levels for 12 to 24 hours.
U.S. Pat. No. 6,083,531 discloses a solid dosage form for oral administration consisting of an active substance, a filler, a binding agent and excipients but specifically no agar. The formulation disintegrates in the mouth in 15 seconds without chewing. However, the tablet is not intended for sublingual use and this disclosure does not envisage morphine or other opioids amongst the suitable active ingredients in the formulation.
U.S. Pat. No. 5,580,876 discloses a method of selectively enhancing the analgesic potency of a bimodally-acting opioid such as morphine and simultaneously attenuating the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. The author suggests in general terms that the formulation may be presented as capsules, tablets, powders, granules or a suspension for oral or sublingual administration. However, there are no examples of suitable sublingual formulations and no disclosure that morphine may be incorporated in such a formulation or indeed how it could be so incorporated.
U.S. Pat. No. 5,411,745 discloses an oral morphine dosage form in which a mixture of morphine sulphate and lactose is coated on to inert beads to provide an immediate release formulation. This disclosure provides of both an immediate and extended duration effect. The formulation is not intended for sublingual delivery and the immediate release beads are loaded into gelatine capsules which are to be swallowed.
Morphine may also be administered by injection. However patients are often averse to receiving repeated injections. Fear of injections may lead children or other patients to endure pain unnecessarily. Injectable dosage forms have also been used for emergency treatment of injuries including by self administration. However self injection kits may be difficult to use correctly dependent on the nature of the user's injury. Furthermore the kit is more bulky than a tablet of equivalent strength so that carriage of single of multiple doses for emergency prophylactic use is less convenient.
One problem of oral morphine dosage forms is due to the bitter taste of morphine. This may interfere with patient compliance. Sublingual absorption may be reduced due to involuntary swallowing by the patient.
There is a need for a need for a formulation containing morphine or a derivative of morphine which can be administered sublingually for the emergency and immediate relief of chronic pain. It is an object of the invention to provide such a formulation. It is a further object to provide a formulation which is convenient to administer, and which can be self administered in emergency situations. One object of the invention is to provide a formulation which is sufficiently palatable for sublingual use and which avoids the tendency of involuntary swallowing by a patient. Another object of the invention is to provide a simple unit-dosage regimen for immediate usage. There is also a need for a formulation which is able to provide a rapid onset of analgesia and the present invention satisfies this need.
According to a second aspect of the present invention there is provided a pharmaceutical sublingual solid dosage form comprising a salt of morphine or a morphine derivative, one or more soluble saccharides as fillers, a binder and a disintegrant.
The morphine salt may be the sulphate, phosphate, hydrochloride, tartrate or less preferably the acetate. Mixtures may be employed.
Various salts of the same active compound often behave quite differently and in ways which are not empirically predictable. This may be due to the different chemical or thermodynamic properties of the active salt compound as a whole. Thus different salts of the same active usually have quite similar physiological effects. However, the intensities of response of a variety of salts may vary widely. In this regard, we have found that the sulphate salt of morphine gives particularly good dissolution and bioavailability. This finding is surprising because the more soluble tartrate salt of morphine is less efficacious. Thus the sulphate salt of morphine is preferred on account of the excellent dissolution of formulations in accordance with this invention both in vitro and in vivo.
The lattice structure of a crystalline molecule can be modified by the presence of a solvent such as water and this may have a profound input on the bulk properties of the active ingredient. Thus the particle size distribution and solubility-related properties will depend upon the hydration state of the active. However, it is not possible to predict the effect of varying the hydration state on these properties. We have found that the pentahydrate of morphine sulphate is particularly advantageous in the sub-lingual formulations of the present invention. A formulation based on the pentahydrate of morphine sulphate in particular shows a remarkable degree of solubility despite the apparent poorer solubility of morphine sulphate compared with other salts of morphine. It is also surprising that a stable solid formulation can be produced from the pentahydrate of morphine sulphate since morphine is known to undergo slow degradation in the presence of air and water vapour. Furthermore the bulk properties facilitate tabletting.
Salts of morphine derivatives which may be employed include salts of diacetyl morphine (diamorphine), and oxycodione, and combinations thereof. The salts may be selected from sulphate, phosphate, hydrochloride, tartrate and acetate. Diamorphine and oxycodone are preferably in the form of hydrochloride salts.
A dosage form in accordance with this invention is preferably rapidly soluble when introduced into the oral cavity. A dissolution time of about two minutes or less is preferred. However morphine salts have an unpleasant bitter taste which makes administration of a soluble dosage form unpleasant and difficult, for example to children. The sweetness of the saccharides reduces the unpalatable taste of the active ingredient. The saccharide or saccharides used are preferably rapidly soluble in saliva.
Tablets in accordance with this invention release 90% of the active ingredient when placed in 500 cm
3
of distilled water for 5 min at 37° C. using the apparatus specified in USP23 with a basket run at a speed of 100 rpm.
In a preferred embodiment the release time is 2 min or less. The onset of analgesia may thus be achieved in only 20 to 30 minutes using the formulations of the present invention. In contrast, traditional oral formulations typically give onset of analgesia in 50 or 60

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