JPH07126163A - Controllably releasable pilocarpine transmitting system - Google Patents

Abstract

PURPOSE: To effectively mitigate the symptoms of xerostomia, xerophthalmia and ocular hypertension without accompanying side actions by administering pilocarpine in a state to keep the pilocarpine concentration in serum at a specific level. CONSTITUTION: Pilocarpine or its salt is administered at a rate to keep the pilocarpine concentration in the serum of the patient to about 5-40 ng/mL for >=6 hr and preferably about 5-25 ng/mL for 8-12 hr. The secretion of saliva is stimulated, the body fluid is supplied to the conjunctiva and cornea and the ocular tension is decreased by keeping the serum concentration at a constant level without giving undesirable effects on the cardiovascular system or causing perspiration, erubescence and gastric cramp. The controlled release pilocarpine preparation contains a homogeneous mixture of pilocarpine and calcium polycarbophil at a rate of 5-30 mg per unit dose. The ratio of calcium polycarbophil to pilocarpine is (10-20):1.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates generally to xerostomia, commonly known as "dry mouth syndrome", and xerophthalmia (dryness of the conjunctiva and cornea). More specifically,
The present invention relates to a method of reducing the symptoms of xerostomia or xerophthalmia in a patient. The invention also relates to a method of reducing high intraocular pressure.

[0002]

2. Description of the Related Art Normally, humans secrete 0.5 to 1 liter of saliva per day. There are large individual differences, but saliva is 65 on average.
% Is secreted by the submandibular gland, 23% by the parotid gland, 8% by the small mucosa and 4% by the sublingual gland. Dry mouth is a condition in which the salivary glands do not secrete a sufficient amount of saliva. This causes discomfort and can be quite heavy in some cases. If saliva is not secreted, the mouth becomes sore that sudden changes in the throat and tongue may occur. Dental caries can occur rapidly, causing the tongue to become smooth, cracked, and susceptible to infection. It is also often tasteless and saliva often contains digestive problems because it contains important digestive enzymes. Continued dry mouth at night disturbs sleep and often (even hourly) wakes up. Further, as a result of xerostomia, periodontal disease and dental caries may increase, and teeth may be lost.

The mouth is one of the most exposed areas of the body to the external environment. Mucous membranes usually form a continuous protective layer in the nose, mouth and throat. In patients with xerostomia, not only does fluid in the mouth decrease, but the amount of mucoprotein and mucopolysaccharide that holds fluid in contact with cells and forms a defense wall against irritation and infection becomes insufficient. The onset of the effects of xerostomia is unnoticed, and there is no clear demarcation of whether or not to have the disease. Moreover, the symptom, degree, and period vary depending on the individual patient. Dry mouth is the most common symptom.
Changes in taste change food selection and cognition. After a change in taste, the taste may be reduced and the taste may disappear altogether.

Mucous tissue in the oral cavity (tongue, gums, mouth, cheeks, etc.) may have sores, ulcers, fissures, swelling, bleeding, capsules, and erosion of the tongue. Loss of saliva causes incomplete digestion, food accumulation, plaque, gum bleeding, denture bridge pain, and extreme bad breath. In addition, it may cause swelling of various oral tissues and difficulty in speech. Lips may be dry or cracked. The incidence of caries may increase dramatically.

It is estimated that there are millions of patients in this state in the United States. However, the actual number of patients with xerostomia is unknown. Until recently, little was known about the prevalence or severity of this problem. Fifty
About 10% of the population over the age of 25 and about 25 of the population over the age of 65
% Is estimated to be dry mouth patients. The majority of patients are women.

Some of the immediate primary causes of xerostomia are autoimmune diseases such as Sjogren's syndrome, radiation therapy, malnutrition, hormonal imbalance, arthritis and aging. Even if the head or neck is treated with as little as 1000 rads of radiation per week, it will be 85 after 6 weeks.
% Patients have xerostomia, and after 3 months 95% have xerostomia. Radiation xerostomia begins immediately, 1
Saliva production decreases by more than 50% after a week, and decreases by more than 75% after 6 weeks of treatment. Dry mouth is progressive, persistent and irreversible, with saliva secretion decreasing by more than 95% after 3 years of irradiation. In patients where only part of the large salivary gland is exposed to the path of ionizing radiation, the unirradiated part proliferates and partially fills the damaged acini. The most severe cases of xerostomia are caused by radiation therapy after head and neck surgery and autoimmune diseases such as lupus, Sjogren's syndrome, and rheumatoid arthritis. For example, PC
Fox et al., J. Am. Dental Assoc. 110: 519-525 (198
See 5).

Decreased salivation after radiation therapy is the "bad news" of cancer, or nausea, headache,
Numerous side effects of chemo- and radiotherapy, such as dysphagia, have a significant impact on a patient's quality of life, which has already been compromised. As mentioned above, saliva is important for maintaining the hard and soft tissues of the mouth or for normally performing oral functions such as taste, swallowing and speech.

Second, xerostomia is a powerful antihypertensive drug,
It is a side effect of administration of more than 400 drugs including antidepressants, antispasmodics, diuretics, muscle relaxants, antipsychotics, appetite suppressants, and Parkinson's disease therapeutics. In addition to salivary gland dysfunction caused by radiotherapy and chemotherapy, many other types of chronic inflammation and other immune disorders characterized by decreased lacrimal glands and salivary gland secretions are known (eg Sjogren's syndrome). This results in keratoconjunctivitis sicca (KC
S) and dry mouth, which are chronic symptoms.

The treatment of Sjogren's syndrome aims at relief of the symptoms and limiting the local damaging effects of chronic xerostomia and xerophthalmia (dry conjunctiva and cornea). Dry eyes respond to the use of artificial tears. Artificial tears may have to be applied every 30 minutes. Sustained-release tear formulations have been reported in the literature with limited success. Soft contact lenses are recommended to protect the cornea but increase the risk of infection.
To prevent evaporation of tears, it has been proposed to cover it with nighttime Saran wrap or put on diving goggles. Although it is difficult to treat xerostomia in patients with Sjogren's syndrome, it is temporarily relieved by frequent intake of water or artificial saliva, chewing gum, candy and the like.

Cases of xerostomia range from mild to slightly dry, to severe, which causes the patient to have significant problems with chewing, swallowing, digestion, speech, etc. Breathing through the mouth can also induce xerostomia. There is also seasonal dry mouth. Other causes of xerostomia, as described in Balslev et al., U.S. Pat. No. 4,438,100, are physiological (eg, aging, menopause, postoperative, dehydration) and psychological (nervous). ).

Until recently, the treatment of xerostomia had major drawbacks. For example, mild symptoms of xerostomia were somewhat alleviated by ingesting liquids, hard candy, and throat lozenge. Food generally increases salivation. Secondary dry mouth effects include sweet candy, lemon drop, peppermint drop,
It is known that it can be widely reduced by foods having sweetness, sourness, or bitterness such as chewing gum. However, since patients with xerostomia are susceptible to dental caries and gum disease, increasing the intake of sugar by the conventional intake of candy and troche is a real problem. Furthermore, liquids or candies are usually ineffective in more severe cases of dry mouth, and even light cases do not provide long-lasting effects.

A common remedy for xerostomia is the use of synthetic saliva. There are many types of artificial saliva available on the market, which contain a combination of alcohol, mineral oil, glycerin, and polyethylene glycol. Based on pig mucin or carboxymethyl cellulose (CMC), all essential electrolytes,
There are many commercial products that contain a buffer and, optionally, flavoring and / or sweetening agents. Usually, electrolytes are potassium, sodium, magnesium, calcium, chlorine, hydrogen carbonate,
Phosphoric acid and fluorine. Most of the artificial saliva, except for mucin-based Danish branded products (Saliva-Orthana) and Dutch-made trials, are CMC-based and contain Orex® (Young Dental), Xero-Lube ( (Registered trademark) (Scherer), Moi-Stir (registered trademark) (Kingswood
Laboratories), and Salivart® (Westport
Marketed under the trademark of Pharmaceuticals). Va-Oralube
(First Texas Labs., Dallas) has a suitable electrolyte and C
It contains sorbitol and fluorine in addition to MC. Moi-St
ir® (Kingswood Co., Toronto) contains a high concentration of sodium and has a mint flavor. Salube (Oraphorm
Co., Australia) is marketed in small dropper bottles. Saliment (Richmond Pharm. Co., Ontario) is also CMC based and lemon flavored. Xero-lube (Scherer
Labs., Dallas, Texas), Artisial (Jouvenal,
Paris, France) and Glandosane (Fresenius, Bad H
(Omburg, West Germany) is sold in regular spray bottles. In addition, glycerin, hydroxyethyl cellulose,
It is known that and polyethylene oxides can also be used as a base for synthetic saliva. However, many patients find that such formulations are irritating or have a bad taste and that the mouth-smoothing effect lasts only for a relatively short time.

Another common remedy for reducing the symptoms of xerostomia is the application of a constant or controlled source of synthetic saliva to the mouth via a permanent or removable dental device. . The palate source of saliva needs to be refilled repeatedly. Detachable maxillary denture with saliva source on the lip is less complicated. The denture has a hole through which it is filled with a syringe, drained during use and washed after each meal. The removable denture with lip has a space for about 3 ml of synthetic saliva. This denture is custom made, so it is expensive, the thickness makes it uncomfortable to wear, and it can be a nuisance to speech, requiring cleaning and refilling several times a day. JA
Toljanic, Quintessence of Dental Technology, 1985
June, pp. 355-358, and The Journal of Prosthetic
Dentistry, Vol. 52, No. 4, pp. 540-544 is illustrated and illustrated and the relevant literature on this issue is cited.
PC as a useful background document for xerostomia
Fox et al. (1985), J. Am. Dental Assoc. 110: 519-52
There is 5 (1985). In addition, some experiments have been conducted with parasympathomimetic drugs, that is, drugs that mimic the actions of the parasympathetic nervous system that regulates salivary secretion. However, these drugs have been reported to have serious side effects as well as problems of dose control. These drugs are generally administered in the form of tablets or capsules. The following are known as drugs that promote salivary secretion. (a) pilocarpine compound (hydrochloride, nitrate, or javolandi leaf or its extract) (b) neostigmine and its bromide, distigmine bromide (Ubretid), pyridostigmine bromide (mestinone; Mestinon) (c) nicotinic acid, Nicotinamide (Nicobion 500;
Nicobion 500), and benzopyrone (Benalot; Vena
lot) (d) Carbachol (drill; Doryl), potassium iodide,
And anethole trithione (Sulfalem S25; Sulf
arlem S 25)

The following are known as drugs that indirectly promote salivary secretion. Ascorbic acid (vitamin C), citric acid tablets, malic acid, lemon glycerin swab (s
wab), and paraffin wax.The above information can be found in Imfeld, Acta Parodontologics, Vol. 13,
4, 1083 / 111-10996-124 (1984), and Vissink et.
al., Ned Tijdschrift Geneesked, Volume 129, Issue 43, 2054
-2057 (1985).

The following references relate to compositions and methods for the treatment of xerostomia. Balslev et al. U.S. Pat. No. 4,4
38,100 discloses viscous artificial saliva containing mucin and oxidative germicide. Mikhail U.S. Pat. No. 4,209,505 discloses a mouthwash containing pilocarpine or a pilocarpine derivative for mitigating dry mouth. The document also notes that various types of therapeutic diets were also used (although with no success) in an attempt to reduce xerostomia.

Ream et al., US Pat. No. 4,151,270 teaches a chewing gum composition formulated to stimulate salivation. The gum contains fructose and organic acids such as adipic acid, ascorbic acid, citric acid, fumaric acid, lactic acid, malic acid or tartaric acid. US Patent No.
No. 4,938,963 discloses a method of treating xerostomia which comprises orally administering to a patient an amount of a liquid eriodictione composition effective to reduce the symptoms of dry mouth. The liquid eriodictione composition comprises a liquid eriodictione extract and a sweetener.

US Pat. No. 4,917,674 discloses a medical device for treating a patient with xerostomia which has two pads for moistening the mouth. Each pad is capable of being saturated with water and has at least one sponge portion for gradually replenishing the water in the mouth.
U.S. Pat. No. 4,906,455 discloses to a patient a gum containing an edible quality organic acid selected from the group consisting of adipic acid, fumaric acid, succinic acid, suberic acid, sebacic acid, azelaic acid and pimelic acid for at least about 20 minutes. A method of treating chewy dry mouth is disclosed.

US Pat. No. 4,820,506 discloses a group consisting of (a) about 2 to about 3% by weight of an edible quality organic acidulant in water, (b) a sugar, a synthetic sweetener, and a reduced sugar-related compound. An edible quality sweetener that is mild to the selected oral microbiota, and
(c) Teach a composition that promotes secretion of human saliva consisting essentially of an aqueous solution in which a saturated calcium phosphate solution is dissolved.

A method for treating xerostomia using pilocarpine taken orally is conventionally known. It has been reported that administration of pilocarpine 5 mg capsules or tablets three to four times a day significantly improves salivary gland function, but also causes many side effects. However, this therapeutic method has a problem that it acts on many parasympathetic nerve action sites in the body because pilocarpine is a very potent parasympathomimetic drug. For this reason, this drug can have many side effects and the therapeutic and toxic blood levels are not too far apart.

It is also known that pilocarpine can be used to treat xerophthalmia (dry conjunctiva and cornea).
In addition, pilocarpine is associated with high intraocular pressure.
It is also used to reduce pressure). Unfortunately, however, treatment of these disorders by administering pilocarpine to patients in need of treatment for xerophthalmia and high intraocular pressure has similar problems to treatment of xerostomia with orally taken pilocarpine. Is accompanied by. Therefore, there is a need for a method for treating xerophthalmia and high intraocular pressure by administering pilocarpine to a patient in a manner that is effective and substantially free of side effects normally associated with pilocarpine treatment, such as sweating, flushing, and gastric cramping. Came.

[0021]

SUMMARY OF THE INVENTION The present invention provides a method of treating a patient suffering from xerostomia, xerophthalmia, or high intraocular pressure. This method of treatment comprises administering to the patient a therapeutically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof in an amount that maintains the patient's pilocarpine serum concentration at about 5 to about 40 ng / ml for at least 6 hours. Become. Maintaining pilocarpine at this serum concentration achieves therapeutically beneficial results for pilocarpine such as effectively alleviating the symptoms of xerostomia, xerophthalmia, and high intraocular pressure.

The present invention also provides a method of preventing xerostomia in a patient undergoing radiation therapy. This method comprises administering a prophylactically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof to the patient's pilocarpine serum concentration of about 5 to about 40 ng / m 2 for at least 6 hours prior to initiating radiation therapy.
Administering to said patient in an amount maintained at l.

The invention further provides a method of preventing xerostomia in a patient undergoing chemotherapy. This method comprises administering a prophylactically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof to the patient's serum concentration of pilocarpine for at least 6 hours at about 5 to about 40 ng / ml prior to initiating chemotherapy.
Comprising administering to said patient in an amount maintained at

The present invention further provides a controlled release formulation of pilocarpine. This formulation has a serum concentration of about 5 to about 4
Pilocarpine can be released at a rate of 0 ng / ml for a long time, for example about 6 hours or more. This formulation contains a homogenous mixture of pilocarpine and calcium polycarbophil in unit dosage form, containing from about 5 to about 30 mg of pilocarpine, wherein the ratio of calcium polycarbophil to pilocarpine is It is about 10: 1 to about 20: 1. Examples of calcium polycarbophil used in the present invention include those described in the United States Pharmacopeia or International Application Publication WO9.
What is described in 2/03124 (or Japanese Patent Publication No. 5-502894) is shown. For example, a calcium salt of polyacrylic acid cross-linked with divinyl glycol may be mentioned.

The present invention has several advantages over prior art pilocarpine tablets. Since pilocarpine is a very powerful parasympathomimetic that acts on many parasympathetic sites in the body, this drug can have many side effects, and therapeutic and toxic blood levels. Are not too far apart. The controlled release delivery described herein provides good and tight control of serum concentrations, thus providing a much better therapeutic approach to managing xerostomia and xerophthalmia.

When pilocarpine is administered in standard oral tablets, capsules, or liquids, it is usually 24 times due to its potent nature and partly due to its short biological half-life.
Dosage 5 mg several times over time. This requires frequent administration. The majority of patients with xerostomia are other elderly patients who are also under heavy stressful physiological conditions. Such conventional oral delivery systems make it very difficult to self-administer accurate and regular dosing.

Preferably, about 0.1 to about 30% by weight carbomer polymer and about 0.1.
Approximately 30% by weight of hydroxymethylcellulose and / or hydroxypropylmethylcellulose is included in the unit dose. Carbomer polymer is polyacrylic acid cross-linked with allyl sucrose. The sustained delivery method according to the present invention requires only one or two administrations every 24 hours or less, and is more accurate and reproducible for patient populations in home or institutional housed environments. Allow better delivery for active dosing.

Most importantly, the prior art oral dosage forms have very high initial blood levels. The reduction in blood concentration depends on many biological factors, and the blood drug concentration usually falls below the therapeutically effective concentration before the next dose is delivered. Thus, prior art orally-administered drugs initially exhibit high blood levels and cause undesired side effects, after which they are below therapeutically effective concentrations, which renders the patient vulnerable to the desired therapeutic effect.
The sustained dosage form of the present invention minimizes the effects of "peaks and valleys" due to its uniform delivery rate and allows for better therapeutic management of xerostomia and xerophthalmia or intraocular pressure.

A fundamental aspect of the invention is to maintain the pilocarpine serum concentration at about 5 to about 40 ng / ml,
It has been discovered that a desired therapeutic effect can be obtained without the above-mentioned undesirable side effects. Preferably, the serum concentration is maintained at about 5 to about 25 ng / ml.
Such serum concentrations are sufficient to stimulate salivation, provide fluid to the conjunctiva and cornea, and relieve intraocular pressure. At the same time, such serum concentrations do not adversely affect the cardiovascular system and cause sweating, flushing, or gastric cramping.

The method for achieving the desired serum concentration is not limited. Preferably, a controlled oral delivery system is employed, but the desired serum concentration is prolonged, for example from about 6 to about 24 hours or more, preferably at least about 8 hours, more preferably at least about 10 hours, most preferably. Other delivery means can be employed, with modifications modified to last at least about 12 hours. Suitable dosage forms include tablets, capsules, powders, granules, and oral solutions or suspensions, oral preparations such as buccal preparations, sublingual preparations, subcutaneous, intramuscular or intravenous preparations, and rectal preparations. Dosage formulations are included. For topical administration, the compounds of the invention are used in the form of creams, ointments or lotions.

In the present specification and claims, the serum pilocarpine concentration means the average concentration determined on the basis of a typical patient, unless otherwise specified. Obviously, the half-life of pilocarpine may vary significantly among individuals because there are individual differences in blood chemistry (enzyme amount and concentration), liver function, and the like. Therefore, even if a person takes the dosage form of the present invention, the desired serum concentration may not be obtained for all desired time. However, such individuals may also benefit from the present invention because the desired serum concentration is maintained for a much longer period of time than is achieved by those who have taken conventional immediate release pilocarpine formulations. it can.

Furthermore, in the case of a specific person, conventional immediate release pilocarpine formulations may exhibit a serum profile reflecting a long release time. In the case of such a person, the administration form of the present invention can further prolong the time at which a desired serum concentration of pilocarpine is exhibited and reduce the number of subsequent administrations required.

Analysis of pilocarpine in plasma is carried out by the following general HPLC analysis method. Blood samples are collected in heparinized tubes containing the appropriate concentration of enzyme inactivator NaF. The sample is centrifuged in a standard clinical centrifuge for approximately 5-10 minutes to separate plasma.
Plasma is removed and additional amount of NaF is added to inactivate the enzyme. Freeze plasma samples until ready for analysis.

The plasma sample is returned to room temperature. The sample is centrifuged again to remove excess sodium fluoride. An aliquot of a plasma sample is taken and a known amount of internal standard-pyrosin
(pilosine) is added. Extract the sample with an aliquot of methylene chloride. Separate the organic layer and evaporate the solvent to dryness at 40 ° C. under a gentle stream of nitrogen. Known amount of 1 mM HCl
Is added and the sample is extracted with ether to remove other organics. The aqueous layer is dried under vacuum to remove residual ether. The sample thus prepared was analyzed by HPLC under the following conditions. Mobile phase: 55/30/15 7 mM potassium phosphate p
Mixture of H4.0 / acetonitrile / methanol Column: 150 cm x 4.6 mm ID 5 micron Sph
Containing erisorb ODS-1 Detection: UV detector 214nm Flow rate 1.2ml / min

If desired, the above conditions may be optimized to obtain the proper separation. The plasma concentration of pilocarpine is determined by comparing the peak height ratio (pilocarpine / internal standard) with the test sample and the standard. The formulations are conveniently in unit dosage form and may be prepared by any method known in the art.

The delivery system in the preferred embodiment is
A unit containing a homogeneous mixture of pilocarpine and calcium polycarbophil, containing from about 5 to about 30 mg pilocarpine in a unit dosage form, and having a ratio of calcium polycarbophil to pilocarpine of from about 10: 1 to about 20: 1. It is a dosage form. The controlled release composition of the present invention may be prepared by granulating or direct compression, direct extrusion, direct blending and direct molding of calcium polycarbophil and pilocarpine or a salt thereof with or without other excipients. It can be directly molded by the direct method.

The sustained release matrix may optionally contain non-edible ingredients which are commonly used in pharmaceutical dosage forms. Accordingly, the composition of the present invention comprises from about 0.1 to about 99% by weight,
One or more excipients may optionally be included, preferably in an amount in the range of about 1 to about 95% by weight. For example, lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, carbomer polymer, hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, acacia (acacia gum), gelatin, croscarmellose sodium, talc, magnesium stearate, stearic acid, etc. And other excipients, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, and pharmaceutically acceptable carriers. Other conventional ingredients that may optionally be included are preservatives, stabilizers, plasticizers, co-solvents, anti-adhesion agents or silica fluidizers or lubricants (eg, Syloid ™ silicon dioxide), and FD & C. (US Food and Drug Cosmetics Act) Colorants.

[0038]

【Example】

Example 1-Preparation of Dosage Form Quantitative Composition of Drugs The following is the quantitative composition of the base granules used to prepare three-step strength pilocarpine hydrochloride controlled release tablets (15 mg, 20 mg and 25 mg) ( USP is the US Pharmacopeia and NF is the abbreviation for the American National Medicines Collection).

[0039]

[Table 1]

(1) If necessary, it was used beyond 5% of the label in order to compensate for the loss in the manufacturing process. (2) The amount of the inactive ingredient was adjusted to 90 to 100% of the indicated value. (3) The alcohol content of the granulation liquid is
It was changed to 0 to 20% V / V according to the drying device. The granulation liquid was removed while drying the granulation mass. (4) The alcohol was replaced with anhydrous alcohol (USP) as required depending on the approval and availability. (5) Optionally hydroxypropyl cellulose (NF) instead of hydroxypropyl methyl cellulose (USP)
Was used.

Quantitative Composition of Drug Pilocarpine Hydrochloride Controlled Release 15 mg, 20 mg and 25 mg tablets were prepared from the basic granules as detailed below. Pilocarpine Hydrochloride Controlled Release 15mg Tablets Final Tablet Weight: 324.00mg ⁽¹⁾ Tablet Machine: 3/8 inch Disc Face-Rasp Edge or Equivalent Pilocarpine Hydrochloride Controlled Release 20mg Tablets Final Tablet Weight: 432. 00mg ⁽¹⁾ Tablet machine: 7/16 inch Disc surface-bevel edge or its equivalent Pilocarpine Hydrochloride Controlled Release 25mg Tablet Final tablet weight: 540.00mg ⁽¹⁾ Tablet machine: 7/16 inch Disc surface -Bevel edge or its equivalent (1) The final tablet weight may be changed within a range of ± 5% based on the pilocarpine hydrochloride content of the basic granules in order to obtain the target drug potency.

Quantitative composition of drug Pilocarpine hydrochloride controlled release 15 mg described below
A tablet composition was prepared and used in the Phase 1 clinical trial of Example 2.

[0043]

[Table 2]

(1) If necessary, more than 5% of the label is used to make up for the loss in the manufacturing process. (2) The amount of the inactive ingredient was adjusted to 90 to 110% of the indicated value. (3) The alcohol content of the granulation liquid is
It was changed to 0 to 30% V / V according to the drying device. The granulation liquid was removed while drying the granulation mass. (4) The alcohol was replaced with anhydrous alcohol (USP) as required depending on the approval and availability. (5) Instead of hydroxypropyl cellulose (NF.1), optionally hydroxypropyl methyl cellulose (US
P) was used.

Example 2 The US Food and Drug Administration Phase I clinical trial was conducted according to the following procedure. Eight healthy volunteers enrolled in the test. Each volunteer took a pilocarpine hydrochloride controlled release 15 mg tablet once every 12 hours for a total of 3 doses.
Subjects were closely monitored as inpatients during the study.

The purpose of this initial clinical trial was to demonstrate the safety and efficacy of a controlled release formulation of pilocarpine hydrochloride which stimulates salivation in 8 normal individuals. The specific purpose was to evaluate multidose resistance, initial efficacy and initial pharmacokinetics. The eight subjects enrolled in this study were generally very healthy and taking no medication other than oral contraceptives. No one complained of symptoms of dry mouth. They showed normal salivary gland function. These volunteers spent three nights in the Carolinas Medical Center as inpatients and were frequently monitored and saliva collected for two days. A heparinized catheter was inserted into the peripheral blood vessel for repeated blood sampling. Subjects took the study drug orally with water three times at 12 hour intervals. About 22
2 (10 ml) blood samples (total 220 ml)
Got over days. The parotid gland and unstimulated whole saliva were repeatedly collected by the direct collection method using a non-invasive Carlson / Crittenden cup. Patients were closely monitored to observe possible adverse effects.

Several laboratory and clinical parameters were measured in order to carefully monitor eight subjects. Initially, all participants underwent a complete physical examination including EKG, urinalysis, complete blood count, electrolyte measurement, HIV test, and liver function test. During the 3-day hospital stay, the physical examination was repeated daily and laboratory examinations including EKG, complete blood count, urinalysis, and electrolyte measurements were repeated on the day the participants took the study drug. Blood pressure, pulse and body temperature were frequently measured during hospitalization. No toxicity or adverse effects were observed by the clinician and were not seen in any subject. The dose was acceptable, and no side effects such as sweating, flushing, and gastric cramps that were usually observed in the immediate release dosage form of pilocarpine hydrochloride were observed in any of the subjects.

The unstimulated total salivary secretion and parotid salivary secretion of the subjects were monitored after the first administration and after the third administration. 8
Saliva volume data obtained from human subjects are shown in Tables 3-8. FIG. 1 shows the average total saliva amount data (8 subjects) measured several times after the first administration and after the third administration at different time intervals.
FIG. 2 and FIG. 3 show the averages of the amounts of saliva of the right and left parotid glands (8 subjects) after one administration and three administrations, respectively. This data indicates that there is stimulation of salivary rate within 1 hour of administration, and that effect appears to persist for at least about 8-12 hours.

Blood samples were collected after one and three doses. Pilocarpine plasma concentration data obtained from 8 subjects are detailed in Tables 9 and 10. Mean plasma concentration data after a single dose and after three doses obtained from eight subjects are shown as a function of time in FIGS. 4 and 5, respectively. This data shows that C _max (maximum concentration) is about 8 for pilocarpine hydrochloride.
It seems to indicate ~ 12 ng / ml. The time to reach C _max is about 1 hour. No toxicity or adverse effects were observed during the study. The pilocarpine hydrochloride controlled release delivery system was well tolerated and no side effects commonly observed with immediate release dosage forms of pilocarpine hydrochloride were observed.

There were no notable changes in the physical examination during the study in all eight participants. Similarly, laboratory parameters remained stable within normal values throughout the study.
There were no symptoms or complaints suggesting that any of the participants experienced any unwanted side effects of pilocarpine. For example, none of the eight subjects complained of increased sweating, flushing or digestive discomfort. In conclusion, all the participants were healthy during the study with no evidence of adverse effects of the study drug according to the above parameters.

[0051]

[Table 3]

[0052]

[Table 4]

[0053]

[Table 5]

[0054]

[Table 6]

[0055]

[Table 7]

[0056]

[Table 8]

[0057]

[Table 9]

[0058]

[Table 10]

[Brief description of drawings]

FIG. 1 is a graph showing average total saliva amount data (8 subjects) measured several times after changing the time interval after single administration and three administrations of the composition of the present invention.

FIG. 2 is a graph showing right parotid salivary volume data (8 subjects) after a single dose and three doses of the composition of the present invention.

FIG. 3 is a graph showing left parotid salivary volume data (8 subjects) after one-time administration and three-time administration of the composition of the present invention.

FIG. 4 is a graph showing mean plasma concentration data as a function of time obtained from 8 subjects after single administration of the composition of the present invention.

FIG. 5 is a graph showing mean plasma concentration data as a function of time obtained from 8 subjects after three doses of the composition of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/32 B 47/38 BC

Claims (10)

[Claims] 1. A therapeutically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof is administered to a patient suffering from xerostomia, xerophthalmia, or high intraocular pressure, the serum concentration of pilocarpine in the patient being at least about 6 hours. A method of treating a patient suffering from xerostomia, xerophthalmia, or elevated intraocular pressure, which comprises administering in an amount maintained at 5 to about 40 ng / ml. 2. The method according to claim 1, wherein the patient is a person receiving radiation therapy and a prophylactically effective amount of pilocarpine is administered before the radiation therapy is started. 3. The method of claim 1, wherein the patient is a recipient of chemotherapy and the prophylactically effective amount of pilocarpine is administered prior to the initiation of chemotherapy. 4. The method according to claim 1, wherein the dry mouth or xerophthalmia is chemically induced dry mouth or xerophthalmia. 5. The method according to claim 1, wherein the dry mouth or xerophthalmia is age-related dry mouth or xerophthalmia. 6. The method according to claim 1, wherein the dry mouth or xerophthalmia is seasonally induced dry mouth or xerophthalmia. 7. A homogenous mixture of pilocarpine and calcium polycarbophil, containing from about 5 to about 30 mg pilocarpine in a unit dosage form, the ratio of calcium polycarbophil to pilocarpine being about 10: Formulation in unit dosage form from 1 to about 20: 1. 8. A carbomer polymer (c) in a unit dosage form.
8. The formulation according to claim 7, which contains about 0.1 to about 30% by weight of an arbomer polymer. 9. The formulation of claim 7 which contains from about 0.1% to about 30% by weight of hydroxymethylcellulose, hydroxypropylmethylcellulose, or a mixture thereof in a unit dosage form. 10. A carbomer polymer in a unit dosage form.
The formulation according to claim 9, which contains about 0.1 to about 30% by weight of (carbomer polymer).