WO1995007672A1

WO1995007672A1 - Rectally-administered, epileptic-seizure-inhibiting composition

Info

Publication number: WO1995007672A1
Application number: PCT/US1994/010301
Authority: WO
Inventors: Victoria A. O'neill; Ralph H. Thomas; Kenneth L. Evenstad; Thomas R. Gorham
Original assignee: Athena Neurosciences, Inc.
Priority date: 1993-09-17
Filing date: 1994-09-12
Publication date: 1995-03-23
Also published as: CA2171627A1; CA2171627C; AU7686394A

Abstract

Described is a rectally administered composition for inhibiting epileptic seizure and its methods of use. The composition contains, in a suitable solvent, an anti-epileptic agent for inhibiting epileptic seizure, a buffer for maintaining pH, and a thickener for imparting a viscosity to the composition effective for rectal administration by injection to a patient in epileptic seizure. Also described is an applicator (10) for the rectal delivery of a medication, e.g., the above described composition, and a method of using the applicator (10). The applicator (10) has a shroud (20) with a longitudinal barrel (30). A cartridge (50) is insertable within the barrel (40), and there are projections (75) for holding the cartridge (50) within the barrel (40). The shroud (20) is made of a plastic material which may have a lubricating additive. The nozzle (30) of the applicator (10) is tapered for delivery of the medication. A seal pin (80) is insertable within a boss (57) of the cartridge (50) to seal the medication from leakage. A tray (21) holds the applicator (10) and lubricant (22).

Description

RECTALLY-ADMINISTERED, EPILEPTIC-SEIZURE-INHIBITING COMPOSITION

FIELD OF THE INVENTION

This invention relates to rectally administered compositions for inhibiting epileptic seizure, to their methods of preparation and application and to an apparatus for the delivery of the compositions.

BACKGROUND OF THE INVENTION

Epilepsy is a paroxysmal, self-sustaining and self-limiting cerebral dysrhythmia characterized by an abnormal and excessive EEG (electroencephalograph) discharge and by a disturbance of consciousness. During an episode of epileptic seizure, there may be involuntary body movement or hyperactivity of the autonomic nervous system. Different kinds of epileptic seizures can display various clinical phenomena and EEG activities. Such variations in clinical phenomena and EEG activities form the basis of the characterization of seizures.

In tonic-clonic seizures (grand mal) , a seizure is characterized by a sequence of tonic spasms of body musculature followed by clonic jerking movement. Tonic spasm is characterized by continuous tension whereas clonic movement refers to alternate muscular contraction and relaxation in rapid succession. In status epilepticus, a succession of grand mal seizures take place without intervening return of consciousness to the individual. See Remington's Pharmaceutical Sciences, Mack Publishing Co., Ch. 56, pp. 1057-1066 and pp. 1072-1081, 18th ed. , 1990, which is incorporated by reference.

Generally, it is desirable to prevent epileptic seizures in humans by maintaining effective drug therapy. However, if seizure takes place, particularly for seizures with extensive tonic-clonic duration, such as status epilepticus , it may be necessary to give prompt treatment to inhibit or moderate the seizure in order to prevent injury to the patient, such as bruises, cuts, broken arms or even damage caused by anoxia. Anti-epileptic drugs (i.e., drugs that inhibit epileptic seizure, either before or after the onset of epileptic seizure) can be given intravenously for acute inhibition of the epileptic seizure. See "Drugs for Epilepsy", The Medical Letter, Vol. 31, Issue 783, 1-4, 1989. However, in situations in which there is involuntarily convulsive movement, intravenous administration of drugs is not desirable because the patient's uncontrolled movement may hinder injection or even cause injuries. Moreover, intravenous injection of diazepam, a preferred anti-epileptic drug, is sometimes painful and can cause thrombophlebitis, an inflammation of a vein associated with thrombus formation. See Selander et al. , Acta Anaesth. Scand. , 25, 516-518 (1981) . A number of drugs are useful as anti-epileptic agents. See Remington's Pharmaceutical Sciences, supra . A convenient way to administer an anti-epileptic drug such as benzodiazepine, e.g. diazepam, is by ingestion so that the drug can be absorbed by the gastro- intestinal tract. Sheth et al . (U.S. Patent No.

4,126,672) describe a sustained-release capsule for oral administration of diazepam. The capsules contain medicaments in combination with a hydrocolloid. Upon contact with gastric fluid, the hydrocolloid hydrates, forming an outside barrier which substantially retains the shape of the capsule. The hydrated layer slowly dissolves, releasing the medicament.

Fish et al. (U.S. Patent No. 4,322,440) describe anti-convulsive compositions and methods of administering such compositions. The compositions are described as capable of being administered orally, as well as parenterally, i.e. via subcutaneous, intramuscular and intravenous injection. Fish et al . also disclose that the anti-convulsive compositions may be administered in the form of a rectal suppository. The suppository may be prepared by incorporating an active anti-convulsive agent into a shapable base material. Suitable suppository bases are described to include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glucose, and fatty acid esters of polyethylene glycol. However, for a patient having jerking movement because of seizure, the above-mentioned routes of drug administration are not practical. Intravenous injection of anti-epileptic agents is difficult. Oral administration is also impractical if the patient has no voluntary control of skeletal muscles. Rectal suppositories are slow-acting and therefore not effective for rendering fast relief of seizure. Therefore, there is a need for an epileptic-seizure- inhibiting composition that can be administered and absorbed quickly and safely.

SUMMARY OF THE INVENTION

The present invention provides a viscous, aqueous-based, epileptic-seizure-inhibiting composition effective to inhibit epileptic seizure. The composition is suitable for rectal administration by injection with a syringe-like applicator. The epileptic-seizure- inhibiting composition is preferably a thickened solution that contains these ingredients: solvent, an anti-epileptic agent for inhibiting epileptic seizure, a pH adjusting agent such as a buffer system for maintaining a pH suitable for rectal administration, and a thickener for imparting a viscosity to the composition effective for rectal administration by injection to a patient in or threatened by epileptic seizure.

A second aspect of the present invention is an applicator assembly which is suitable for rectal administration of the above compositions . The applicator has a cartridge which contains the medication, i.e., the above-described composition, and a shroud having a barrel which encases the cartridge. The cartridge is preferably made of glass. The shroud is preferably made of a plastic material . There are retention means for holding the cartridge within the barrel, and a pair of wing members which extend outwardly from the applicator to provide finger grips for the person administering the medication. The shroud can be made of a plastic material which has a lubricating additive. Alternatively, a suitable external lubricant may be used. The applicator also includes seal means for preventing leakage of the medication, which preferably is a seal pin which extends through the nozzle and is insertable within a boss of the cartridge.

The invention is also directed to a method of using the delivery apparatus, comprising the steps of: removing a seal pin from engagement with an opening in the cartridge, inserting the nozzle into the patient's rectum, and depressing the plunger to expel the medication from the cartridge.

One advantage of the applicator of the present invention is that it is able to deliver an accurate dosage of medication. The medication is contained within a closed cartridge or capsule which contains a precise unit dose of the medication. The complete depression of the plunger assures the user that the entire dosage of medication has been delivered.

Additionally, the user is able to examine the transparent or translucent applicator and know that the entire medication has been dispensed. After use, there is minimal to no residual of the medication left in the applicator. Furthermore, there is no withdrawal of the medication from the rectum once the applicator's plunger has been depressed. Thus, there can be no accidental suction of the medication back into the delivery apparatus from the vacuum caused by movement of the plunger.

Another advantage of the applicator of the present invention is that there are no sharp edges, mold parting lines, or sharp 90° segments which could irritate the rectal tissues. Rather, the applicator is preferably made of a relatively flexible, elastic and deformable plastic material which is smooth and tapered to facilitate its usage and the patient's comfort. The applicator has a guard flange which prevents the insertion of the applicator's barrel past the anus. Additionally, the applicator has a locking mechanism which locks the capsule within the shroud, which facilitates ease of usage and cleanliness.

Another advantage of the present invention is that the medication can be administered quickly. The person simply opens the package containing the applicator, removes the seal pin from the end of the applicator, inserts the tip member of the applicator into the patient's rectum, and applies pressure to the plunger to deliver the medication into the rectum of the patient. An optional step is the application of an external lubricant to the applicator's tip prior to insertion. The applicator is designed so that it can be operated with only one hand. The applicator contains a premeasured volume of medication, so that the entire contents can be utilized without the need for measuring.

Furthermore, the applicator is simple in construction, durable and reliable in use, and economic in manufacture and assembly. A glass cartridge may be utilized for containing the medication, with a plastic shroud providing protection from breakage of the cartridge.

These features along with other advantages will become subsequently apparent, based on the details of construction and operation that is more fully described herein, reference being made to the accompanying drawings, wherein like numerals refer to like parts throughout.

Brief Description of the Drawings FIGURE 1 is an exploded perspective view of the applicator for rectal administration of a medication. FIGURE 2 is a cross-sectional, exploded view of the applicator of FIGURE 1.

FIGURE 3 is a cross-sectional view of the applicator of FIGURE 1, illustrating the applicator before use. FIGURE 4 is a cross-sectional view of the applicator shown in FIGURES 1-3, illustrating the applicator's position after use.

FIGURE 5 is a side elevational view of the sealing pin of the present invention. FIGURE 6 is a perspective view of a tray which is suitable for packaging the present invention.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention is a composition for inhibiting epileptic seizures in a patient, such as status epilepticus seizures, acute cluster epilepsy seizures, acute repitctue seizures and febrile seizures. The composition is preferably a viscous solution or suspension, which is suitable for rectal insertion using a syringe-like applicator, yet is capable of being retained inside the patient's rectum without substantial leakage or drainage therefrom. The composition is useful for inhibiting or moderating an epileptic seizure in a patient during seizure. However, it can also be used to prevent the onset of seizure. A. Anti-Epileptic Agent

A wide variety of anti-epileptic agents are known in the art. Many may be utilized in the epileptic-seizure-inhibiting composition of this invention. Representative examples of effective anti- epileptic agents include ethynyl amines such as deprenyl, eldeprine and eidepryl barbiturates such as mephobarbital, febarbamate, primidone, and phenobarbital sodium, benzodiazepines such as carbamezepine, lorazepam, and diazepam, hydantoins such as phenytoin sodium, mephenytoin and ethotoin BP, oxazolidinediones such as paramethadione and trimethadione, succinimides such as phensuximide and methsuximide, and dipropylacetic acid derivatives such as valproic acid, vaproate sodium and divalproex sodium. See Remington' s Pharmaceutical Sciences, supra .

All anti-epileptic agents are not equally effective to inhibit all epilepsies because there are many different types of epilepsies, each having different etiology. Therefore, in the practice of the present invention, it is desirable to individualize their use in the drug therapy based on the particular seizure type and patient response. It is known that, for example, for grand mal seizures, and simple and partial complex seizures, drugs such as phenytoin, carbamazepine or valproate are more effective. For petit mal seizures, valproate is more effective.

When a patient is in epileptic seizure, in order to minimize injury to the patient due to tonic spasm and clonic movement, prompt administration of medication is required to inhibit the seizure. For seizures involving tonic spasm and clonic movement, particularly grand mal and status epilepticus seizures, even though many anti-epileptic agents, such as phenobarbital, can be used in the invention, the drug of choice is a benzodiazepine, particularly diazepam. Because of their relaxing effect in skeletal muscles, benzodiazepines, particularly diazepam, are also useful in the present invention for treating various types of epilepsies involving skeletal muscle contraction or spasm. In treating epilepsy, occasionally, it may be preferable to use two or more anti-epileptic agents in the composition of the present invention. When two or more anti-epileptic agents are present in an epileptic- seizure-inhibiting composition, it is important to ensure that there is no deleterious interaction between the anti-epileptic agents so as not to reduce the effectiveness of the anti-epileptic agents or cause toxicity to the patient. Routine and standard procedures known in the art can be used to determine such interactions.

Typically, the total amount of anti-epileptic agent or agents present in the composition is about 0.1- 2.5 wt-% of the total composition, preferably about 0.25-1.5 wt-% to about 7.5 wt-%. In the preferred embodiment in which diazepam is the only anti-epileptic agent in the composition, the concentration of diazepam is typically about 0.25-0.75 wt-% of the composition.

Preferably, a dose of epileptic-seizure- inhibiting composition is selected so that the effective amount of the anti-epileptic agent is in a suitable volume for a particular patient. Thus, a single dose of a composition of the present invention contains an amount of an anti-epileptic agent which is therapeutically effective to inhibit an epileptic seizure. This amount will depend on the particular anti-epileptic agent used. For commercially available anti-epileptic agents, information on the therapeutically effective amount for inhibiting epileptic seizure is available to the public. Typically, the present composition can be administered so that single doses of diazepam of about 7.5 mg to 20 mg are delivered to an adult, so as to achieve a dose in the range of 0.2-0.5 mg/kg, and about 2 mg to 20 mg are delivered to a child, so as to achieve a dose of about 0.3 to 1.0 mg/kg. The amount can vary depending on the size and physical condition of the individual. The volume of the present epileptic- seizure-inhibiting composition to be administered also will vary with different patients. As a general guideline for using the composition of the present invention, e.g., wherein 0.5 wt-% diazepam is the anti- epileptic agent, typically the dosage is about 1.5 ml to about 5 ml for an adult (> 12 years) , preferably about 2-4 ml; and about 0.5 ml to about 4.0 ml for a child (under 12 years) , preferably about 1.0 to 3.0 ml.

B. Thickener

The epileptic-seizure-inhibiting composition of the present invention contains an amount of a thickener effective for rendering the consistency of the composition effective for rectal administration to a patient in epileptic seizure by injection. To be effective as an injectable, rectally administered epileptic-seizure-inhibiting composition, the present composition preferably has a viscosity such that it can be quickly administered by injection, yet once administered, does not tend to leak out of or drain from the anus. If the viscosity of the composition is too low, because of the fluid consistency of the composition and movement of the patient, the composition may leak out of the rectum after administration. Such a leakage would make it difficult to produce the seizure- inhibiting effect desired. On the other hand, if the viscosity of the composition is too high, there may be difficulty in administering the composition into the rectum of a patient by injection. The viscosity generally will be low enough such that it will flow through, for example, a syringe- type applicator as described below. When administered into the rectum of a patient, the composition will remain substantially inside the rectum without substantially leaking out, and spread over the rectal mucosa without clumping. Generally, the leakage is less than 20% over 4 hours.

The composition typically has an apparent viscosity of about 1,000 to about 8,000 centipoise (cps) , and more preferably, about 2,000 to about 6,000 cps, as measured using a Brookfield viscometer DV-IILV, spindle #3 at 12 rpm, sample size 150 ml at 21°C.

The desired viscosity of the composition may be maintained using a physiologically-acceptable thickener. Representative examples of thickeners that can be used include cellulose ethers such as methylcellulose, carboxymethylcellulose, e.g., CMC-MV from Amend Drug and Chemical Co. ; hydroxypropylcellulose, e.g., KLUCEL LF, GF, and MF from Aqualon; hydroxypropylmethylcellulose, e.g., METHOCEL E4MP, K100LVP, and E50LVP from Dow Chemical Co.; bio- gums, e.g., xanthan gum RHODIGEL from R.T. Vanderbilt Co.; carboxy vinyl polymers, e.g., Carbopol 934P from B.F. Goodrich Co.; and like. Preferred thickeners include hydroxypropylmethylcelluloses and hydroxypro- pylcelluloses with hydroxypropyl methylcellulose (molecular weight of about 22,000) being the most preferred.

Generally, an effective amount of a suitable thickener or thickeners is used to provide a viscosity within the desired range. The amount of a particular thickener used in the epileptic-seizure-inhibiting composition is dependent on the particular thickener used. Typically, the concentration of a suitable thickener such as a cellulose ether is about 1-10 wt-% of the composition, preferably about 2.5 to 7.5 wt-%. For embodiments containing other anti- epileptic agents, based on the above-described viscosity and thickener information, the effective amount of a thickener selected may be determined by routine experimentation using the above-mentioned thickeners and an aqueous solution of a selected anti-epileptic agent, buffer system, and solubilizing agent if needed.

C. pH Adjusting Agent

The natural pH in the rectum is about 7.0. The optimal pH for stability for some anti-epileptic agents is slightly lower than 7. For example, for diazepam stability, the optimal pH is about 5.5. It is preferred that the pH of the present composition be adjusted to a value that is acceptable for rectal administration and stability of the anti-epileptic agent. Therefore, typically, the pH of the present composition containing diazepam will be neutral or mildly acidic, e.g., about 5.5 to 7.5. Preferably, the pH is about 6.2 to 7.2.

The pH of the rectally administered composition of the present invention can be maintained by a pH-adjusting agent, e.g., by a buffer system. A typical buffer system used in the invention contains organic acids and their corresponding sodium or potassium salts, with sodium salts being preferred. Examples of effective buffering systems are citric acids-sodium citrate, acetic acid-sodium acetate, benzoic acid-sodium benzoate, the preferred being benzoic acid-sodium benzoate. As with solubilizers, pH adjusting agents compatible with particular anti- epileptic agents are known in the art and often an anti- epileptic agent supplied in solution form contains suitable pH adjusting agents. One can vary the pH of the epileptic-seizure-inhibiting composition by fine- tuning the amount of the pH adjusting agents. For the preferred embodiment with diazepam as the anti-epileptic agent, the concentration of benzoic acid can be about

0.01 to 10 wt-% of the composition and the concentration of sodium benzoate can be about 1 to 10 wt-% of the composition to maintain the pH at about 5.5 to about 7.5. Preferably, the concentration of benzoic acid is about 0.01 to about 1.0 wt-% of the composition and the composition of sodium benzoate is about 3 to about 7 wt- % of the composition.

Solvent

As used herein, the term "solvent" encompasses water, one or more organic co-solvents or mixtures thereof.

(i) . Water

Water acts as a carrier for the different ingredients in the composition of the present invention. Generally, any commonly available source of water can be used. Preferably, the water is deionized water or distilled water, which has very little "hardness" ions that can lead to precipitation in the composition.

Typically, water can constitute about 25 to 95 wt-% of the composition, most preferably, about 25 to 50 wt-% of the composition. With the selected thickeners in the above-described concentration ranges, the present composition typically has a flowable viscous consistency.

(ii) . Organic Solvent

In order for the anti-epileptic agent to be absorbed by the rectum, and for aesthetic reasons, the anti-epileptic agent preferably is maintained in solution in the present composition. Because some of the anti-epileptic agents may not be readily soluble in water, the water can be combined with one or more nontoxic, water-miscible organic solvents which solubilize the anti-epileptic agents and inhibit the precipitation thereof. Depending on the particular anti-epileptic agent, different organic solvents may be used. In the preferred case, wherein diazepam is the anti-epileptic agent, 1-2 nontoxic polyols or alkanols such as, propylene glycol and/or ethyl alcohol may be used as the organic solvent.

To facilitate the absorption of the anti- epileptic agent by the rectum, an organic solvent that can act as a physiologically-acceptable liquid surfactant can be selected to be included in the epileptic-seizure-inhibiting composition. An effective surfactant can modify the surface tension of the composition of the invention and facilitate coating of the epithelial cells in the rectum by the composition. Polyols such as propylene glycol and glycerol can act as surfactants or plasticizers in the composition.

Generally, the organic solvent or solvents are used in amounts effective to solubilize the anti-epilep¬ tic agent and to inhibit precipitation thereof in the epileptic-seizure-inhibiting composition, e.g., about 25 to 75 wt-% of a polyol or polyol-alkanol mixture may be employed. In the preferred embodiment in which the epileptic-seizure-inhibiting composition contains diazepam as the anti-epileptic agent, typically, propylene glycol is present at a concentration of about 25 wt-% to about 60 wt-% of the composition, and ethyl alcohol is present at a concentration of about 5 wt-% to about 15 wt-%. In some cases, the solvent used in the present composition can consist entirely of one or more nontoxic organic solvents.

E. Optional Ingredients A physiologically-acceptable preservative can be optionally included in the epileptic-seizure- inhibiting composition to extend the shelf-life of the composition against bacterial attack. Benzyl alcohol is the preferred preservative, although other preservatives, for example, thimerosal, chlorobutanol, methyl parabens, propyl parabens and benzalkonium chloride may also be used. The concentration of the preservative needed in a composition varies with the preservative selected. Typically, a preservative is present in the epileptic-seizure-inhibiting composition at a concentration of about 0.01 wt-% to about 2.5 wt-% of the composition. For benzyl alcohol, the preferred concentration is about 1 wt-% to about 2.0 wt-%.

Ingredients of the composition of the present invention are preferably selected to avoid substances that can have a chemical reaction with the active anti- epileptic agent in the composition. The selection of ingredients and the proper concentration of such ingredients to avoid chemical reaction can be accomplished based on the present invention and by following standard and routine procedures, and reference to standard pharmacological texts and publications.

.Another aspect of the selection of ingredients for such a composition can be to improve the aesthetic appeal of the composition. Generally, it is preferred that the composition be relatively clear. Therefore, the selection of the ingredients, their concentrations, and the pH of the composition is preferably done in a manner consistent with maintaining the composition precipitation-free.

______ Preparation of the Epileptic-seizure-inhibiting

Composition

The composition of the invention can be prepared by mixing the ingredients according to generally accepted procedures for formulating pharmaceutical mixtures. Generally, the ingredients can be mixed in a mixer, blender, or other standard mixing device to produce a concentrated mixture. Sufficient time for mixing and procedures for elimination of lumps is used to ensure that a homogenous mixture is formed. Additional amounts of water can be added to obtain the desired concentration. The concentration of the buffering ingredients may also be adjusted to obtain the desired pH in the final composition. Alternatively, if the proper amounts of the various ingredients have been . determined by prior experiments, these amounts can be added and mixed together in a mixing vessel without pH adjustment.

G. Administration of the Epileptic-seizure-inhibiting Composition

The composition of the present invention can be administered or applied to the rectum of a patient in anticipation of potential or imminent seizure or during the seizure period. While a single dose may be administered which is effective to inhibit the seizure, prophylactic doses can be given every eight hours to prevent the onset of seizures. Therefore, a single unit dose of about a 1 ml to about a 6 ml volume of the composition will be administered, which contains the necessary effective amount of the anti-epileptic agent. The epileptic-seizure-inhibiting composition is preferably applied to the rectum by an applicator.

The term "medication" used in the description of the applicator of the present invention is synonymous with the above-defined composition.

Referring to the Drawings, the applicator 10 has a housing or shroud 20. The shroud 20 has a cylindrical barrel 40 with a first, forward end 41 and a second, rear end 42. The barrel 40 has a longitudinal bore therethrough which has a rear opening 78 proximate the second end 42. The shroud 20 also has a nozzle or delivery member 30 which is elongated and tapered. The nozzle 30 is preferably integral with the barrel 40 proximate the front end 41 of the barrel 40. The integral nozzle 30 and barrel 40 form a shroud 20 which may be produced in several different sizes. In the preferred embodiment, two shrouds are provided: one having a smaller nozzle and barrel for a child, and another having a larger nozzle and barrel for an. adult. Alternatively, the nozzle 30 and barrel 40 are separate members which are operatively interconnected before use of the applicator 10. If the nozzle 30 is a separate member, a particular size nozzle 30 can be chosen depending upon the age and size of the patient. The volume of the barrel is preferably in the range of 1 ml to 10 ml. As an example, a 1.5 inch (3.8 cm) length nozzle 30 and a 3 ml size barrel 40 could be used for a person who weighs up to 150 pounds, whereas a 2 inch nozzle (5.1 cm) and 5 ml size barrel 40 could be used for a person who weighs over 150 pounds.

The delivery member 30 is adapted for insertion into the rectum of the individual to be treated. The nozzle 30 may be about 3 centimeters to about 7 centimeters long. It is relatively flexible, and the tip 35 of the delivery member 30 is blunt enough to obviate the risk of puncturing a patient's tissue when the delivery member 30 is inserted into the rectum. The delivery member 30 has an internal hollow passage 31 which terminates in the open tip 35. The nozzle passage 31 is in fluid communication with the bore of the barrel 40. The passage 31 has a constant diameter for most of the length of the nozzle 30. At the end of the delivery member 30 opposite the tip 35 is a larger diameter channel 72, which is formed within the delivery member 30 and is in communication with the passage 31 and the bore of the barrel 40. At the juncture between the delivery member 30 and the barrel 40 is an annular guard flange 43 to prevent insertion of the barrel 40 past the anus.

As shown in Figures 1-4, the applicator 10 has a cylindrical cartridge or vial 50 which contains a predetermined volume of medication (not shown) . The cartridge 50 has a central body portion 55, a boss 57 at its front end, and an outwardly-extending flange 53 at the opposite end. The flange 53 may be round or any other suitable shape, but is oval in the preferred embodiment. The outside diameter of the cartridge's body is sized and configured to slip-fit within the bore of the barrel 40. The cartridge's length is slightly less than the length of the barrel 40 and is of a size such that when the cartridge 50 is inserted into the barrel 40, the luer portion 57 of the cartridge 50 extends slightly out of the barrel 40 and into the channel or bore 72 inside the nozzle 30. The length and diameter of the cartridge 50 is large enough to accommodate the necessary volume of medication to be delivered.

The cartridge 50 should be made of a material which does not absorb or chemically react with the agents in the medical composition. This is particularly important if the medication is stored in the cartridge 50 for an extended period of time. In the preferred embodiment, the cartridge 50 is made of glass. Alternatively, a suitable plastic polymer or copolymer could be utilized, such as PET (polyethyleneterepthalate copolymer resin) , PETE (the PET copolymer, extrusion molding grade) , PETG (the same PET copolymer, general injection molding grade) , or SELAR (the trademark for an amorphous nylon resin, sold by the DuPont Company) .

In the preferred embodiment, the applicator housing 20 is made of a suitable thermoplastic polymer. Broad classes of useful thermoplastic polymers include vinyl polymers, polyamides, polyimides, polyamideimide, block polyamides-polyethers, polysulfones, polyolefins, and mixtures thereof including copolymers and polymer mixtures. Preferably, the applicator housing is made of a thermoplastic polymer comprising a polyolefin such as a polyethylene or polypropylene. Useful polyethylenes and polypropylenes include those having a low, medium, and high density as polyethylenes and polypropylenes particularly preferred are copolymers of polyethylene and polypropylene sold under the brand names Polyallomer™ and Marlex™. The most preferred thermoplastic resin is medium density polypropylene, which allows the shroud 20 to be manufactured as an integral piece in an injection molding process. This material also provides sufficient flexibility for ease of use. Alternatively, other polyolefin thermoplastics could be used.

In the preferred embodiment, the shroud 20 is made of a transparent or translucent material, although the shroud 20 could be opaque or colored. Because the glass cartridge 50 is surrounded by the plastic barrel 40, the risk of glass breakage and injury to the patient is minimized.

A single unit dose of about 1/2 ml to about 6 ml volume of the medication can be administered with the applicator 10. (The maximum capacity of the rectal cavity is approximately 10 ml.) For example, the preferred dosages for an anti-epileptic medication are about 0.5-4.0 ml for a child and about 1.5-5.0 ml for an adult . The volume of the medication which is prepackaged in the cartridge 50 varies according to the type of medication, the patient's body weight and whether the patient is a child or an adult. In the preferred embodiment, there may be two standard sized applicators 10, one of which has a larger barrel 40 and correspondingly larger cartridge 50; and the other of which has a smaller barrel 40 and correspondingly smaller cartridge 50. Each of these applicators 10 is able to store and deliver a different premeasured volume of medications depending upon how much medication the cartridge contains.

Suitable medications in addition to the compositions above described for use with the applicator 10 include, but are not limited to, pain control medications (such as morphine sulphate, acetaminophen, ketorolac tromethamine and aspirin) , nausea medications (such as prochlor perazine hydrochloride, sumatriptan, promethazine hydrochloride, triethylperazine maleate, and trimethobenzamide hydrochloride) and anti-epileptic medications (such as diazepam) .

The applicator 10 has pressuring means for expelling the medication, preferably a plunger member 60 which can be slidably engaged within the bore of the barrel 40. The plunger 60 is utilized to urge the medication out of the cartridge 50 and through the delivery member 30. The plunger 60 is able to slide on the surface of the lumenal wall of the applicator 10. The plunger 60 has a stopper 63 and a plunger rod 64 attached to the stopper 63. The distal end of the plunger 60 has a cap 66 which forms a circumferential flange. Preferably, the stopper 63 is made of a relatively soft, deformable material, such as rubber. Alternatively, the stopper 63 could be made of a copolymer or a combination of plastic and rubber. At its outer end, the stopper 63 has internal screw threads (not shown) . The stopper's screw threads are engagable with complementary external screw threads 95 on the forward end of the plunger rod 64. If the plunger 60 and stopper 63 are not in screw thread engagement, they could be attachable by a snap-in or key-lock design.

The rear end 42 of the cylindrical barrel 40 has a pair of wing members 70 which extend radially from the barrel 40 and are preferably integral with the barrel 40. The wings or finger grips 70 are sized and configured to support the fingers of the person administering the medication. The finger grips 70 allow the apparatus 10 to be used with one hand. Having two finger grips 70 instead of one continuous circular finger grip can provide better flexibility to enable snap-fitting of the cartridge flange 53 onto the end of the barrel 40. The inner end of each finger grip 70 terminates in an inner ridge 73 which is proximate the periphery of the barrel's rear opening 78. Retention means are preferably provided for retaining the cartridge 50 within the barrel 40. The rear opening 78 of the barrel 40 is defined by a circular perimeter. Around the perimeter at spaced intervals are a plurality of snap retention formations, such as nubs or barbs 75. The nubs 75 are resilient projections which extend radially inwardly. Each nub or barb 75 is sized and configured to snap-fit with the flange 53 on the cartridge 50. The nubs 75 therefore permit the cartridge 50 to be inserted into the barrel 40 with ease, but prevent the cartridge 50 from being inadvertently withdrawn from the barrel 40. In the preferred embodiment, there are a total of four nubs 75 spaced at 90° from each other. With this design, the cartridge 50 may be inserted into the shroud at any orientation in order to provide an interlock between the oval flange 53 and the nubs 75. Thus, the user saves time because the cartridge need not be precisely aligned. In addition, the nubs 75 may help in the centering and insertion of the cartridge 50 into the shroud 20 if the assembly is done by a machine at relatively high speed.

In the preferred embodiment, the glass cartridge 50 is not reusable, because it is locked into the barrel 40 of the plastic shroud 20 after the applicator 10 has been used. The plastic shroud 20 and glass cartridge 50 within the shroud 20 are therefore discarded as a unit after use. Alternatively, the retention means for holding the cartridge 50 within the barrel 40 could be releasable, so that the cartridge 50 could be removed after use. With this type of design, the cartridges 50 would be disposable, but the applicator shroud 20 would be re-usable after sterilization thereof. The delivery member 30 is lubricated before insertion into the patient's rectum. This may be done by applying a lubricating jelly to the exterior of the nozzle 30. In one embodiment of the invention, the plastic material for the housing 20 has a lubricant additive, such as a stearate or silicone material. With this alternative, the lubricant is mixed with the plastic resin prior to the molding process. The amount of lubricant added depends upon the migration requirements. In this manner, the nozzle 30 is lubricated and insertion of the nozzle 30 is facilitated. The applicator apparatus 10 is preferably contained in suitable packaging, such as a box, envelope or plastic blister pack, along with suitable instructions such as a label or package insert . In the preferred embodiment, the applicator 10 is packaged in a thermoformed tray as shown in Figure 6. Preferably, the tray 21 is made of polyvinyl chloride although other thermoplastic resins could be used. The tray has a pressure-sensitive lid (not shown) which may be peeled off. In the preferred embodiment, the lid is bonded to the tray by radio frequency sealing, although induction sealing or ultrasonic sealing could also be utilized. The lid may be either transparent or opaque. This tray construction could be adopted to an application requiring a sterile environment, if necessary. The applicator 10 is locked into the thermoformed packaging 21, which prevents any leaking or accidental activation. In the preferred embodiment, the thermoformed plastic tray 21 has a plurality of nibs (not shown) which lock the applicator 10 into position and prevent the applicator 10 from accidentally being activated during the shipping and storage handling steps. The tray 21 has cut-out areas which correspond to the size and configuration of the applicator 10. The tray 21 also has a cutout 23 for providing finger access to the applicator 10 at the time of removal from the tray 21. In one embodiment, the tray has a pocket 22 formed therein, which is suitable for containing a lubricating jelly. The lubricant pocket 22 is sealed by the same pressure-sensitive lid which covers the rest of the tray 21. Thus, the pocket 22 is automatically opened when the user peels off the lid. The user may then dip the nozzle 30 into the lubricant, prior to the insertion of the nozzle 30 into the anus of the rectum.

Prior to the time of usage, the rear end of the cartridge 50 is sealed by engagement of the stopper 63 within the cartridge 50. The cartridge 50 is filled with medication to the desired volume, and the stopper 63 is positioned in place by means of a vacuum. In this manner, the cartridge 50 is prefilled under clean or sterile conditions, as in a pharmaceutical laboratory.

In the preferred embodiment, the cartridge 50 is inserted into the syringe barrel 40 at a central supply point. Alternatively, the cartridge 50 may be inserted at the place where the applicator 10 is to be used. That is, the shroud 20 and cartridge 50 may be packaged as separate members, and the cartridge 50 may be inserted within the barrel 40 at the time of usage. With this embodiment, the boss 57 of the cartridge 50 is covered with a releasable seal, such as a rubber tip (not shown) , which is removed before the cartridge 50 is inserted into the barrel 40.

Preferably, the boss or luer 57 of the cartridge 50 is sealed by means of a seal pin 80 which extends through the nozzle 30. The seal pin 80 is of a slightly larger diameter than the inside diameter of the luer 57. The seal pin 80 has an elongated staff member 81 which terminates in a head 82. As shown in Figure 3, the pin head 82 abuts against and closes off the tip opening 35, and the end 96 of the staff member 81 is insertable within the boss 57 to close off and seal the cartridge 50 with an interference fit. The seal pin 80 has several centering ribs 97 which guide the seal pin 80 into the luer 57 for a proper interference fit, and serve to seal the medication within the cartridge 50. The ribs 97 are raised fins or beads which are molded integrally with the rest of the seal pin 80. The seal pin 80 is made of a polyethylene material which provides adequate friction sealing and controlled alignment of the seal pin 80 within the glass boss 57.

If the seal pin 80 is not utilized, an alternative sealing means is used. For example, a suitable one-way valve (not shown) may be positioned within the rear end of the delivery member 30. The valve opens to permit flow of medication 90 only when pressure from the plunger 60 is applied. .An example of a suitable valve would be a disc valve made of a rubber compound, or a duck-bill valve. To assemble the applicator apparatus 10, a rubber tip is applied to the boss 57 and the glass cartridge 50 is pre-filled with the medication. The plunger stopper 63 is positioned within the cartridge 50, with the plunger rod 64 being screwed into the stopper 63. At a later point, the rubber tip is removed from the boss 57 and the cartridge 50 is inserted within the plastic shroud 20. Preferably, the seal pin 80 is preassembled within the plastic shroud 20 before the assembled cartridge assembly is inserted into the shroud 20. The ribs 97 hold the seal pin 80 in position within the shroud nozzle 30. The cartridge 50 is inserted within the shroud 20 such that the seal pin 80 fits within the luer 57 of the cartridge 50.

In operation and at the point of usage, the applicator 10 is removed from its thermoformed tray or package 21. The configuration of the applicator 10 shown in FIGURE 3 depicts the applicator 10 prior to use. The seal pin 80 is removed from the applicator 10 by grasping the head 82 of the pin 80, and the seal pin 80 is discarded. The delivery member 30 is then inserted into the rectum of the patient so that the flange 43 of the applicator 10 is snug with the anus. The medication is administered by the operator manually engaging the finger grips 70 and applying pressure on the plunger 60, thereby forcing the medication out of the cartridge 50 and through the tip 35, and into the rectum of the patient.

The medication in the cartridge 50 is delivered into the rectum within a span of about two to three seconds. After the medication has been administered, the delivery member 30 is withdrawn from the patient's rectum. Because the glass tube 50 is clear and the plastic shroud 20 is translucent, it is apparent to the user that the product has been dispensed. The volume remaining in the applicator 10 after use is approximately 0.1-0.5 ml. The user is therefore assured that the proper dosage has been delivered to the patient.

Once the plunger 60 has been depressed, it is very difficult, if not impossible, to thereafter withdraw the plunger 60 from the applicator barrel 40. This is because the plunger cap 66 is recessed within the shroud 20 and there is no part of the plunger 60 within the user's grasp. Also, in the preferred embodiment, there are plunger retention means or projections 76 which extend inwardly. These projections 76 flex outwardly as the cartridge 50 is being inserted into the shroud 20, but lock the cartridge 50 into position when it is fully inserted into the shroud 20. This feature of the invention prevents the user from accidentally withdrawing or asphyxiating medication out of the patient's rectum after the administration of the medication.

H. Characteristics of the Composition

While orally and intravenously administered epileptic-seizure-inhibiting compositions are not conveniently given to a patient in seizure with tonic spasm and clonic movement, the composition of the present invention is advantageously so employed. The composition of this invention is effective to inhibit epileptic seizure because it can be administered into the rectum in seconds and the anti-epileptic agent in the composition is absorbed quickly by the rectum.

As a viscous substance, once inserted into the rectum, the composition can easily spread over a large surface area in the rectum. For this reason, the composition of the present invention has advantages over suppositories. Suppositories are slow to soften, and therefore, the time it takes for the anti-epileptic agent to be absorbed may be unreasonably long for the purpose of inhibiting seizure that is in progress. Clinical studies has shown that diazepam suppositories are inappropriate where a rapid effect is required (see Hughes et al . , Aust J. Hosp. Pharm., 14:2, 73-75 (1984)) . The composition of the present invention, however, can provide much faster absorption of the anti- epileptic agent. The consistency of the composition of the present invention is also viscous enough to substantially prevent leakage from the rectum. A patient in seizure often is in convulsion and frequently has no control over the rectal sphincter. Such a patient is not capable of voluntarily tightening the sphincter muscle to retain the liquid anti-epileptic drug inside the rectum. The convulsive movement exacerbates the problem of leakage of the liquid anti- epileptic agent. If an anti-epileptic agents is given rectally in liquid form, the seizure-inhibiting effect may not be realized because a low viscosity liquid has a tendency to leak out from the anus .

In intravenously administration of epileptic- seizure-inhibiting compositions, the pH of the epileptic-seizure-inhibiting composition is maintained at a range that is compatible with the intravenous route of administration. The pH for an intravenously administered composition is adjusted to such a narrow range so as not to significantly affect the pH of the body. Generally, the pH of such an intravenous composition is maintained at about 6.2 to 7. However, the optimal pH for stability of the anti-epileptic agent may be at a different range. For a composition that is administered rectally, a wider range of pH may be suitable because there is a less risk of adversely affecting the pH of the blood. As a result, the epileptic-seizure-inhibiting composition can have a longer shelf life than intravenous solutions.

To illustrate the specific elements of the invention, the following examples are given. These examples are for illustrative purpose only and not to be unduly considered as limitations of this invention.

Example 1

Epileptic-seizure-inhibiting Composition

Propylene glycol USP (10.6 kg) , ethyl alcohol (2.65 kg) , and benzyl alcohol (0.398 kg) were added to a clean stainless steel mixing vessel and mixed at 730 rpm at 25°C, and then benzoic acid USP (0.305 kg) was added into the mixture through a 20 mesh screen and mixed for ten minutes. Diazepam, USP (0.128 kg) , was added into the mixture and mixed for an additional 20 minutes.

Hydroxypropylmethyl cellulose, METHOCEL™ E50 LVP (1.113 kg) obtained from Dow Chemical Co., Midland, MI was added.

In a separate vessel, sodium benzoate, NF (1.02 kg) was mixed with deionized water (10.286 kg) until the sodium benzoate was dissolved.

The resulting sodium benzoate solution was then added into the mixture in the mixing vessel and mixed for 50 minutes at 1640 rpm. The resulting composition can be used to fill a 1-5 ml cartridge of an applicator such as that shown in FIGURE 1 and FIGURE 2. The cartridge is then inserted into the applicator, tip end first. Product is prevented from leaking out of the nozzle by a membrane, pin or other device. This applicator is then packaged in a kit with instructions for use by the caregiver. Alternately, the cartridge may be filled, sealed with a stopper on the barren end and cap on the tip end. The applicator is then packaged in a kit with the filled cartridge. The cartridge can be assembled into the applicator at the time of use by the caregiver by removing the tip cap and inserting the cartridge into the applicator. The device is then ready for administration.

Example 2 Epileptic-seizure-inhibiting Composition

An epileptic-seizure-inhibiting composition is made using a procedure analogous to that of Example 1 except 1.0 kg of phenobarbital sodium, USP (Windthrop) is used instead of 0.128 kg of diazepam. This composition can be used to inhibit, for example, grand mal seizure.

Example 3

Epileptic-seizure-inhibiting Composition An epileptic-seizure-inhibiting composition is made using a procedure analogous to that of Example 1 except 0.128 kg of phenytoin sodium, USP (Park-Davis) is used instead of 0.128 kg of diazepam.

This composition can be used to inhibit, for example, grand mal seizure.

Example 4

Bioavailability Study

A comparative, randomized single-dose 2-way crossover bioavailability with the diazepam viscous

® solution of Example 1 and Roche diazepam (valium ) injectable solution was conducted using as subjects 18 healthy adult males, age 18-45 years. A dosage of 15 mg of the composition of Example 1 was administered

® rectally and Roche valium was administered intravenously by injection. The results showed that the absolute bioavailability for the present rectal solution was

90.4% relative to the Roche injectable solution. Half- lives were similar and the maximum serum concentrations of diazepam (447 ng/ml for the present composition and 584 ng/ml for the Roche injectable) were both above the effective therapeutic concentration of approximately 200 ng/ml . The rectally administered dose is rapidly absorbed but the maximum concentration absorbed is lower than the injectable dose, lessening concern for adverse effects, such as respiratory arrest.

Example 5

Use of the Epileptic-seizure-inhibiting Composition When a adult patient is observed to have an epileptic seizure attack, the kit of Example 1 is opened and the applicator assembled by opening the sealed end of the cartridge and inserting the cartridge into the cylindrical barrel of the applicator, open end first, with the plunger extending out of the end of the barrel distal to the elongated, hollow member. The elongated, hollow member of the applicator is inserted past the anus into the rectum of the patient. Then the composition in the cartridge is then delivered into the rectum, within a span of about 2 seconds, by applying pressure on the plunger to force the composition past the open end of the cartridge and through the elongated, hollow member. After the composition has been delivered into the rectum, the elongated, hollow member is withdrawn from the rectum of the patient. The present invention has been described in the foregoing specification. It is to be understood that modifications and alterations of the invention can be made without departing from the spirit and scope of the invention. The embodiments are presented for illustrative purposes only, and are not to be interpreted as limiting the scope of the invention.

Claims

WHAT IS CLAIMED IS :

1. A viscous, epileptic-seizure-inhibiting composition comprising:

(a) an anti-epileptic agent in an amount effective to inhibit epileptic seizure;

(b) a buffer system in an amount effective to maintain the pH of the composition at a value acceptable for rectal administration and to stabilize the anti- epileptic agent;

(c) a thickener in an amount effective to impart a viscosity to the composition so that it is suitable for administration by rectal injection to a human patient; and

(d) the balance, solvent.

2. The composition of claim 1 comprising:

(a) about 0.25-0.75 wt-% diazepam;

(b) a buffer system in an amount effective to maintain the pH of the composition at about 5.5-7.5;

(c) about 1-10 wt-% cellulose ether thickener;

(d) about 25-75 wt-% of a non-toxic water- miscible organic solvent; and

(e) the balance, water.

3. A method of inhibiting epileptic seizure in a patient, comprising administering into the rectum of the patient by injection an effective amount of a viscous, epileptic-seizure-inhibiting composition which comprises a composition of claim 1, wherein the composition substantially remains within the rectum following injection.

4. An applicator for rectal administration of a medication, comprising:

(a) a cartridge containing the medication;

(b) a shroud including a barrel which is sized and configured to encase said cartridge, a nozzle that is integral with said barrel, retention means for holding said cartridge within said barrel, and a pair of wing members which extend outwardly from said applicator; and

(c) seal means for preventing leakage of the medication through said nozzle.

5. The applicator of claim 4, wherein the medication is a viscous, epileptic-seizure-inhibiting composition comprising:

(d) the balance, solvent.

7. The applicator of claim 4, wherein the medication comprises :

(a) about 0.25-0.75 wt-% diazepam;

(c) about 1-10 wt-% cellulose ether thickener;

(d) about 25-75 wt-% of a non-toxic water- miscible organic solvent; and (e) the balance, water.

8. An applicator for rectal administration of a medication, comprising:

(a) a cartridge containing the medication, said cartridge having a boss;

(b) a shroud including a barrel which is sized and configured to encase said cartridge, said shroud including a nozzle integral with said barrel, said nozzle including a flange for positioning of said applicator; and

(c) a seal pin having two ends, one end of said seal pin being insertable within said boss for sealing of said cartridge.

9. The applicator of claim 8, wherein the medication is a viscous, epileptic-seizure-inhibiting composition comprising:

(d) the balance, solvent.

10. The applicator of claim 8, wherein the medication comprises :

(a) about 0.25-0.75 wt-% diazepam;

(c) about 1-10 wt-% cellulose ether thickener;

(d) about 25-75 wt-% of a non-toxic water- miscible organic solvent; and

(e) the balance, water.

11. A method of assembling an applicator for dispensing a medication, comprising the steps of:

(a) filling a cartridge with the medication, one end of said cartridge being sealed with a stopper;

(b) inserting a seal pin into a nozzle member of a shroud;

(c) screwing a plunger rod into said stopper; and

(d) inserting said cartridge into said applicator, wherein an end of said cartridge is sealed with said seal pin.