HK1127994A - The use of a cholinesterase inhibitor in the treatment of xerostomia - Google Patents

Description

Treatment of xerostomia with cholinesterase inhibitors

The present application is a divisional application of a patent application having application number 96199706.0, application date 1996, 25/11, entitled "treatment of xerostomia with cholinesterase inhibitors".

Technical Field

The present invention relates to a new use of a class of known compounds for the topical administration of cholinesterase inhibitors to the oral mucosa for the treatment of xerostomia, and a method for the treatment of xerostomia.

Background

Xerostomia, or xerostomia, is a commonly experienced condition characterized by a reduction or cessation of salivary secretion.

Saliva is secreted by many salivary glands, as long as there are parotid, submandibular and sublingual glands, and many tiny accessory salivary glands just below the oral mucosa.

Saliva is used for the sole function of keeping the mucous membranes of the mouth moist, moistening food during chewing, protecting the teeth and aiding the primary digestion of starch.

Thus, the immediate consequences of xerostomia include chewing, swallowing, difficulty speaking, and interruption of sleep. More seriously, however, xerostomia has been found to cause ulceration of the oral mucosa, dental diseases including caries, increased incidence of candida, infections with staphylococcus, and halitosis caused by the latter.

Xerostomia has a variety of etiologies, and can be further classified according to the department of etiology.

Primary xerostomia, which results from a pathological process (e.g. atrophy or disease) that leads to hypofunction of the salivary glands. Primary xerostomia is also prevalent in patients suffering from rheumatism, such as Sjogren's syndrome, and in patients undergoing radiation therapy for head and neck cancer.

The incidence of primary xerostomia is known to increase with age. For example, in sweden, more than 15% of people over 50 years of age complain of dry mouth. This increased to 25% in people over 70 years of age, and 33% in people over 80 years of age. Up to 40% of the elderly population hospitalized in sweden suffer from xerostomia.

Secondary xerostomia is a particularly common side effect encountered by patients taking certain medications. It is believed that about half of all medications cause some degree of xerostomia and that this problem is particularly prevalent in patients taking antidepressants and psychiatric medications.

Currently, there are very few existing treatments for xerostomia, including only some synthetic mucins (e.g., calcium carboxymethylcellulose, hydroxymethylcellulose (hypromellose), and methylcellulose), and agents that act by lowering the viscosity of saliva in the patient's mouth (e.g., calcium thiocyanate, 1, 6-hexanediamine,).

pilocarpine hydrochloride has recently been used for the systemic treatment of xerostomia caused by radiation therapy. However, pilocarpine has also been found to cause some adverse side effects related to cardiac, blood pressure and digestive function. Even small daily doses of pilocarpine can cause profuse sweating.

U.S. patent No.5,387,614 discloses systemic treatment of xerostomia in patients with a ligand for the Sigma receptor, i.e., an N, N-disubstituted alkylaniline.

Cholinesterase inhibitors (hereinafter referred to as CEIs) are known to be particularly useful in the treatment of diseases such as myasthenia gravis, glaucoma and intestinal paralysis.

One cholinesterase inhibitor pyridostigmine has been used in patients with xerostomia, see, e.g., Ferguson, m.m., Oral surg. 75, 191. Oral administration of the sustained release tablet to a patient can cause increased salivary flow and increased tears with different responses among different patients.

Thus, there remains a need for a xerostomia therapeutic agent that is effective and does not produce significant side effects.

We have now surprisingly found that CEIs are highly effective in the treatment of xerostomia and, to stimulate salivation and to eliminate xerostomia, are administered directly to the oral mucosa, in particular to the parasialytic gland, without causing any significant side effects.

Disclosure of Invention

Accordingly, the invention herein provides the use of CEI in the formulation of a medicament for topical administration to the oral mucosa for the treatment of xerostomia.

The term "xerostomia" is understood by the person skilled in the art to include all forms of primary and secondary xerostomia that are common in human or animal patients, regardless of the cause. Thus, the term will be understood to include any condition that manifests as xerostomia and/or reduced or stopped salivation.

In particular we have found that when CEI is administered topically to the oral mucosa of a patient suffering from, or susceptible to, xerostomia, salivary output is increased.

Thus, according to another aspect of the present invention there is provided a method of treating xerostomia which comprises topically administering to the oral mucosa of a mammalian patient suffering from, or susceptible to, such a condition a therapeutically effective amount of CEI.

The CEIs include physostigmine, neostigmine bromide, neostigmine sulfate, pyridostigmine, (3 aS-cis) -1, 2, 3, 3a, 8, 8a, -hexahydro-1, 3a, 8-trimethylpyrrolo [2, 3-b ] indol-5-yl-3, 4-dihydro-2 (1H) isoquinoline carboxylate (see example 54 of International Patent Application No. SE92/00873), and (3 aS-cis) -1, 2, 3, 3a, 8, 8a, -hexahydro-1, 3a, 8-trimethylpyrrolo [2, 3-b ] indol-5-ol (see U.S. Pat. No.5,187,165), or combinations thereof.

In accordance with the present invention, there is provided a method of treating xerostomia comprising topically administering to the oral mucosa of a mammalian patient suffering from, or susceptible to, such a condition, a therapeutically effective amount of CEI.

We have found that use of CEI on the oral mucosa stimulates the oral "accessory" salivary glands to produce saliva, which, as those skilled in the art know, are located just below the oral mucosa. Further we have found that topical application of CEI to the oral mucosa_SWill result in saliva secretion sufficient to alleviate xerostomia without causing significant side effects such as sweating.

CEI_SMay be co-formulated according to known techniques with other ingredients commonly used for topical administration of pharmaceutically active compounds.

Formulations suitable for topical administration include solutions, particularly aqueous solutions. The active compounds can also be formulated for topical administration in the form of sustained release tablets, which can be placed (e.g., by sticking) in close proximity to the various salivary glands. Other topical dosage forms that may be mentioned include chewing gums, lozenges, mouthwashes, and pastilles.

Preferred topical administration forms are sustained release tablets.

Other ingredients that may be used in a topical formulation will depend on the particular CEI and the topical mode of administration employed.

The amount of the one or more pharmaceutically active compounds in the topical formulation will depend primarily on the particular CEI or CEIs included, and the topical mode of administration employed. For example, when the administration form is by means of an aqueous solution, the content of the pharmaceutically active ingredient is generally from 0.01 to 100mg/ml, preferably from 0.05 to 25mg/ml, and particularly preferably from 0.1 to 10 mg/ml. In general the daily dosage of CEI may be in the range of from 0.1 to 100mg of active ingredient, for example from 0.2 to 25mg, preferably from 0.5 to 10 mg.

CEI_SCan be co-formulated with other active ingredients designed for the treatment of xerostomia, such as synthetic mucins, viscosity-lowering agents (e.g., Mucidan), such as pilocarpine.

The advantage of the treatment according to the invention is CEI_SIs particularly effective in alleviating the symptoms of xerostomia without exhibiting significant side effects. The therapeutic methods of the invention also have the ability to incorporate CEI as desired_STopical application to the oral mucosa.

The treatment of the present invention also has the following advantages over previous methods of administration for the treatment of xerostomia: CEI_STarget cells in their oral parasials are reached more quickly, in higher concentrations, and remain viable for a longer period of time.

In the treatment methods of the present invention, the CEIs are less toxic than the active ingredients previously used to treat xerostomia, or may have other beneficial pharmacological properties.

Drawings

FIG. 1 shows buccal salivary gland secretion of physostigmine (1 mg/ml; n.5).

Test of

Test A

Salivary secretion of ferret salivary gland:

ferrets (obtained from Mr sting Held, Bjarshog, sweden) were fasted overnight and then general anesthetized. All salivary ducts of the major salivary glands were ligated or catheterized. Salivary secretion from catheterized salivary glands was monitored.

To obtain background values, a piece of pre-weighed dry filter paper is placed on the inside of one cheek of the animal, taken out after 5 minutes and then weighed, and the procedure is repeated twice.

The substance to be tested is topically applied to the buccal mucosa in the form of an aqueous solution for more than 5 minutes. Buccal saliva was collected on a pre-weighed fresh piece of filter paper, which was replaced every 5 minutes until saliva secretion returned to the background value determined in advance.

Heart rate and blood pressure were recorded continuously.

Test B

Salivary secretion of the accessory salivary gland of human volunteers:

to obtain background values, a piece of pre-weighed dry filter paper sheet was placed inside the lower lip of healthy volunteers. Saliva was collected over a fixed period of time.

Several drops of the test substance were then applied as an aqueous solution to the inner side of the lower lip and saliva was collected from the site over an equal period of time using a piece of pre-weighed filter paper.

The amount of saliva collected in each case was compared.

After this test procedure, the patient is asked whether he or she experiences any adverse side effects during or after the use of the active substance.

The invention can be illustrated by the following examples:

example 1

Physostigmine (aqueous, 0.1-10mg/ml) was tested as described above for test A.

The lowest dose (0.1mg/ml) produced a maximum secretion of 13. mu.l over a period of 5 minutes, and the highest dose (10mg/ml) produced a maximum secretion of 90. mu.l.

Secretion returned to background values 15 minutes after physostigmine was used at the lowest dose (3 μ l in 5 minutes) and 100 minutes after the highest dose.

Only mild reductions in blood pressure and heart rate were observed after administration of the highest dose.

Buccal gland salivary secretion was plotted against time after administration at the dose of 1mg/ml, and is shown in FIG. 1.

Example 2

Neostigmine bromide (in water, 0.1-10mg/ml) was tested as in test A above. The highest dose (10mg/ml) produced a maximum secretion of 60. mu.l over a period of 5 minutes, with the secretory response lasting about 20 minutes.

Example 3

Neostigmine sulfate (in water, 0.1-10mg/ml) was tested as described above for test method A. The highest dose (10mg/ml) produced a maximum secretion of 130. mu.l over a period of 5 minutes, with the secretory response lasting about 20 minutes.

Example 4

Two healthy persons were tested with physostigmine (aqueous solution, 0.1-1mg/ml) according to test method B above. An increase in local salivation to approximately 2-fold of background values was observed following dosing, with a sustained increase of approximately 15 minutes. No side effects were observed.

Claims (4)

1. Use of a cholinesterase inhibitor for the manufacture of a medicament for topical administration to the oral mucosa for the treatment of xerostomia.

2. The use as claimed in claim 1, wherein the cholinesterase inhibitor is physostigmine.

3. A pharmaceutical formulation for topical administration to the oral mucosa for the treatment of xerostomia wherein the active ingredient is a cholinesterase inhibitor.

4. A pharmaceutical formulation as claimed in claim 3 wherein the cholinesterase inhibitor is physostigmine.