AU596741B2 - Anti-nausea and anti-emetic agents - Google Patents

Description

596741 S F Ref: 56396 FORM COMIMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class 00 o 09 0 0 *O 0' h Complete Specification Lodged: Accepted: Published: Priority: Related Art: 4 1 S. Name and Address of Applicant: o a 0o Nastech Pharmaceutical Company, Inc.

800 Veterans Memorial Highway Hauppauge New York 11788 UNITED STATES OF AMERICA Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Address for Service: 0 0 Complete Specification for the invention entitled: ANTI-NAUSEA AND ANTI-EMETIC AGENTS The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3 0 005~0*0 o 0 0 00 00 0 9090 00040 0400 0 00 0 0 000 0 0 044000 0 9 BACKGROUND OF INVENTION i Q0 0 0 60 0 4 90 0 0 0 I 4 0 0 0 i o 0 4 1 10 Field of the Invention The .esent invention relates to a novel method of administering therapeutic agents including antihistamines and anti-nausea and anti-emetic agents and to novel dosage forms containing such agents adapted for nasal admini'stration.

The invention provides a novel method of administering therapeutic agents that are antihistaminic or inhibit nausea and emesis in mammals. Nausea and emesis are often induced by stimulation of either'the chemoreceptor trigger zone or the emesis (or vomiting) center in the central nervous system. Such stimulation can be caused by afferent stimulation tactile pharyngeal impulses, labrynthine disturbances, motion, increased intracranial pressure, pain, distention of viscera or psychologic factors) or blood born emetic substances as seen during pregnancy, cancer chemotherapy, uremria, radiation therapy, electrolyte and endocrine disturbances, or the presence of chemical emetic substances).

1 The invention further provides dosage forms of those agents which are adapted for nasal administration and which include solutions, suspensions, sustained release formulations, gels and ointments. The therapeutic agents include selected antihistamines including those with antitussive, anticholenergic, antipruritic, sedative and antianxiety properties, as well as selected antinausea and antiemetic agents.

Background Art 0 0 0 0 0 A number of antihistaminic, antinausea and antiemetic agents 0 are known. Such agents are widely used therapeutically, chiefly io the treatment of vertigo, motion-sickness, hypersensitivity o phenomena (anaphylaxis and allergy), rhinitis, sinusitis and gastroesophageal reflux diseases. Unfortunately, many of these 0 00 agents when used: cause undesirable side effects, are t 0 0 0° 0 inefficiently and variably absorbed from current dosage forms, 0 I 0 0 are difficult or inconvenient to administer in the current dosage forms after the onset of emesis or nausea, and have 4. delayed onset of pharmacological activity when administered by current dosage forms. It has now been unexpectedly discovered that these pharmacologically active agents can be administered by 0 0: nasal delivery to provide: enhanced bioavailability, minimized 0 0 0 0° variations in blood levels, more rapid onset of activity and reduced dosages when compared to most current methods of administration oral, subcutaneous, intra-mus,-ular or by ;way of suppository).

Nasal delivery of therapeutic agents has been well known for a number of years. See, for example, U.S. Patents 4,428,883; 4,284,648 and 4,394,390; and PCT application International Publication Number W083/00286. See also, Hussain et al, J.

Pharm. Sci. 68, No. 8, 2196 (1979); 69 1240 (1980) and 69 1411 (1980).

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The PCT document describes nasal compositions for the administration of scopalamine, a parasympathetic blocking agent but fails to tach or recognize that a therapeutic response can be elicited at a dosage level which is only a fraction of that normally employed.

While nasal administration of certain therapeutic agents to o mammals, especially humans is known, it is not a necessary conclusion from such knowledge that all therapeutic agents can be no usefully administered by this route. In fact it has been shown 1W that many drugs cannot be usefully administered by the nasal route. It certainly is not a suggestion that the compounds of 0"4 0° this invention can be usefully administered nasally to achieve enhanced bioavailability and sustained therapeutic blood levels.

0 a 0 SZatuchinin, et al, for example reported in LHRH Peptides as 0o Female and Male Contraceptives, Harper Row, Publishers (1976) 00.4 that, although LHRH peptides were effective when administered intranasally, a much higher dose was required than with parenteral administration.

Childrey and Essex reported an immediate and marked pressor a2Q response upon injection of 1 mg of nicotine in dogs, but little or no effect on injections of the samp or larger amounts into the sinus of dogs or cats. Arch. Otolaryngol., 14 564 (1931).

SHussain et al have concluded that peptides are poorly absorbed through the nasal mucosa. See Transnasal Systemic Medications, Edited by Y.W. Chien, Elsevier Science Publishers, 1985, page 121 et seq, at page 122.

Physicians routinely utilize steriods such as flunisolide for topica3 treatment of nasal polyps because they are not rapidly absorbed and manifest excellent topical antiinflammatory with minimal systemic activity.

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A

4 SUMMARY OF THE INVENTION The invention provides a method of eliciting a systemic, therapeutic antihistaminic, antinausea or antiemetic response in a mammal which comprises administering nasally to said mammal a systemically, therapeutically effective antihistaminic, antinausea or antiemetic amount of a therapeutic agent which is selected from the group consisting of cimetidine, ranitidine, terfenadine, diphenylhydramine, carbinoxamine, clemastine, phenytoloxamine, doxylamine, dimenhydrinate, tripelennamine, pyrilamine, pheniramine, chlorpheniramine, brompheniramine, dexchlorpheniramine, triprolldine, promethazine, trimeprazine, propiomazine, methdilazine, cyproheptidine, azatidine, diphenylpyraline, phenindamine, hydroxyzine, cyclizine, chlorcyclizine, buclizine, meclizine, trimethobenzamide, benzquinamide, metoclopramide, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable nasal composition.

It has been discovered that known antinausea and antiemetic agents as well as antihistamines with both H 1 and H 2 receptor activity can be usefully administered to mammals in novel compositions at extremely low OOO dosage levels to elicit a systemic therapeutic response and to provide V enhanced bloavailability, minimized variations in blood levels, more rapid 120 onset of activity, ease of administration, and reduced side effects 1 o compared to most current methods of administration. Specifically, the blood levels of a therapeutic agent achieved by nasal administration can be substantially the same as the levels achievable with oral dosage units containing as much as ten times the amount of the same therapeutic agent.

°-oo 5 The nasal administration process of this invention is significantly more S convenient than parenteral administration. Simple aerosol containers, or eye droppers which can be easily carried in a pocket or purse can be used S for delivery. This should be compared with hypodermic needles which are difficult to use and repugnant to most people. In many jurisdictions it is illegal to transport them and have become associated with the transmittal l of diseases such as AIDS or hepatitis when improperly used.

tThe invention further provides a pharmaceutically acceptable composition suitable for nasal administration and for absorption essentially through the nasal mucosa to obtain a systemic therapeutic antihistaminic, antinausea or antiemetic response in a mammal which comprises a therapeutic agent which is selected from the group consisting C -7 .1 4A of cimetidine, ranitidine, terfenadine, diphenylhydramine, carbinoxamine, clemastine, phenytoloxamine, doxylamine, dimenhydrinate, tripelennamine, pyrilamine, pheniramine, chlorpheniramine, brompheniramine, dexchlorpheniramine, triprolidine, promethazine, trimeprazine, propiomazine, methdilazine, cyproheptidine, azatidine, diphenylpyraline, phenindamine, hydroxyzine, cyclizine, chlorcyclizine, buclizine, meclizine, trimethobenzamide, benzquinamide, metoclopramide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier, diluent, excipient and/or adjuvant.

More specifically the compositions of the invention are for nasal administration and contain a therapeutically effective amount of the selected therapeutic agent or agents. They are conveniently provided as isotonic aqueous solutions, suspensions or viscous compositions which may be buffered to a selected pH. The viscous compositions may be in the form of gels, lotions, ointments, creams and the like and will typically contain a sufficient amount of a thickening agent so that the viscosity is from about 2500 to 6500 cps, although more viscous compositions, 4 o ~r o 4 4 4oJi.

4444 4 4 t) 4 4 4444n 4 44o 44 4

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a 0 4 04 STtMI/779V even up to 10,000 cps may be employed. The preferred compositions have a viscosity of 2500 to 5000 cps, since above that range they become more difficult to administer.

Liquid sprays and drops are normally easier to prepare than gels and other viscous compositions. Additionally, they are somewhat more convenient to administer, especially in multi-dose situations. -Viscous compositions, on the other hand are much preferred in the practice of this invention since they can be formulated within the appropriate viscosity range to provide longer contact periods with the nasal mucosa and reduce the o o amount of therapeutic agent per dosage unit necessary to achieve S the desired result.

o DETAILED DESCRIPTION OF THE INVENTION 0 1 As is well known to those skilled in the art, there is an overlapping of activity amongst antihistaminic, antinausea and a0 O antiemetic drugs. Several drugs which may be used as "0 antihistamines are also known to have antinausea and antiemetic effects. These compounds include members of the meclizine family such as meclizine and cyclizine. Cimetidine and ranitidine are antihistamines with H2-receptor activity. They are used principally to control gastric secretions sometimes associated o s with nausea and emesis. Some antihistamines such as doxylamine are also useful as sedatives. Hydroxyzine, a piperazine type antihistamine is useful both as a sedative and as an antianxiety agent. It is specifically intended to include such therapeutic agents within the scope of this invention. Antihistamines are utilized for a wide variety of medical purposes including, for example, treatment of Lrticaria, hay fevere bronchial asthma, vasomoter rhinitis, and some dermatoses. The compositions of this invention are useful for the administration for all such utilities and others where antihistamines are currently usefully employed.

5 Certain antihistamines such as terfenadine do not appear to be members of any specific class yet identified. It is included in the ambit of the invention.

Antihistamines which may be usefully employed in the practice of this invention include ethanolamines such as diphenyhydramine, carbinoxamine, clemastine, phenytoloxamine, doxylamine and dimenhydrinate; ethylenediamines such as tripelennamine, and pyrilamine; alkylamines such as pheniramine chlorpheniramine, brompheniramine, dexchlorpheniramine and So triprolidine; phenothiazines such as promethazine, trimeprazine, oo. propiomazine and methdilazine; piperdines such as cyproheptidine, azatadine, diphenylpyraline and phenindamine; piperazines such as hydroxyzine, cyclizine, chlorcyclizine,. buclizine and meclizine.

This last mentioned class of antihistamines are often referred to as the meclizine family of antihistamines or as meclizines. They S will be so identified herein. They are preferred for"t'-f.e practice of this invention because of their ready availability 6o 0 o 0 and because they are highly active, even at low concentrations.

a o Antiemetic agents useful in the practice of this invention include members of the meclizine family such as those mentioned above, trimethobenzamide, benzquinamide, metoclopramide, S diphenhydramine, dimenhydrinate, promethazine.

0 06 Antihistamines with H 2 -receptor activity which are useful in the practice of this invention include cimetidine and ranitidine.

Any pharmaceutically acceptable form of the therapeutic agents can be employed, i.e. the free base or a pharmaceutically acceptable salt thereof including, for example maleates, fumarates, succinates and hydrochlorides such as cyclizine hydrochloride, cyclizine acetate, diphenhydramine hydrochloride, meclizine hydrochloride, promethazine hydrochloride, etc.

Generally the selected therapeutic agent is employed in the 6 I instant compositions and method in the pharmaceutically acceptable form which has previously been found most advantageous for oral or parenteral use.

The structural formulae for certain of the agents utilized in the present invention are set forth below: C 6

H

Cg 6 5 -CHOCH 2

CH

2 NH (C 3 2 0 0 OQ 4 o 0 9 4u 00 4 Dimenhydrinate 00 0 4n 9 00 0 0 04 4 4 049 0 U4 Cyclizine Meclizine (CgH 5 2 CH-N N-CH 3

CH

C1 CH N N- CH 2

I

2 Meclizine Hydrochloride

C

6

H

7 Trirnethoben zamide OCR 3

(CHR

3 2 NCH 2

CHR

2 OC2NO-- OCR 3 OCR 3

OCOCR

3 (C 2

H

5 2 0 0 9 a) 'a coo,, 0 ca, a'a 0 0 0 000 9 0 a, 0 0 C 00 0 0 a) a 0 CH 3 0 Ben zquinamxide CH3

CONHCR

2 CH N (C 2

RH)

Me to clopramidce

NHR

2 a, 0 0 Diphenhydramine Bromphniamifle c 05 Ctl 3 CFROCl 2 CRl 2

N

C

6

H-

5 CH 3 CCICRN (CH 3 2 -N I CBt 8- (CH 3 2 Promethazine Cyproheptadiie 0 0 0 0

IR

Doxylarnine Al 0

CHR

3

-OH

2 CH 2 N(CH 3 2 CH 3 N C-OCH CH iN(C" 3 N CH 2

-CQI-

Doxylamine Succinate 2 N(CH 3 2 Tripelennane Methapyrilene Methapyrilene Hydrochloride 0 0 0 0 0 0 0 0 0 a 0 0 0 CH 2

NCH

2 CH 2 N(C-1 3 2 S ,,CH NCH CH N (CU 3

H

rL 2 2 2Cl- N1 I 0 00,0 0* 0, 0 00 S I S a a as C1 a CH-N 2 3)3 fluclizine 1L0 Chioroyclizine, Hydrochloride H -Cl

N

IC

CH 3 OCH 2 CH 2 N(CH3) 2 Carbinoxamine Maleate 4 040 40~4 0* 00 0 00 00 1 4 4 044 0 0 9 0 0 0 0 0 04 00.' 0 00 00 CH- COOH 11

CR-COO-

Triprolidone N C C

C

00 0 0

CH-I

2 Cl TriPrOlidone Hydrochloride J2.

C-

2

C

6 ONxCH CH N(CH 3 ?h eny ito loxam in e CH 3 Pyrilai'ive Maleate

CH-

2 CH 2 N (CH 3 )2 I

/N

04 4 4 4 4 4 4 44

CH-COOH

CH- COOc 6 10 I

CHCII

2 CH 2 N (CH 3 2

CH-COOR

I I CH- COO- Pheniranine maleate

CH-COOH'

11 CH-COO- Clorphenirainine Maleate 12 I 7 CH 3 Uri 2CRCH 2 N(CH1 3 2 'N "'N1 Trirneprazine r~n444q 4 4 4 #4 44 4 "44 4 44 44 4 444 4 4 4 4 4 44 44 4 4 44 4 64 4 4 4 44 Cimetidine Ranitidine H 3

N

NCN

CH 3 NHCNHCH 2 CH 2 SCH 2 (CH 2

NCH

2 0 CH SCH, H 2

NHCNHCH

3 4 444444 4 4

I

4 41 4 44 I-C C 3 Methdilazine 13 These therapeutic agents and their r.ethods of preparation are well known.

In accordance with the present invention, the selected drugs are administered nasally to humans or other mammals with results considerably superior tc those obtained with oral administration in terms of more rapid absorption as well as enhanced drug bioavailability and minimization of blood level variations, thus enabling use of these drugs at lower dosage levels and, possibly, with fewer side effects than was previously possible except in the case of intravenous administration. It would appear that SD, these selected drugs are rapidly absorbed from the nasal mucosa into systemic blood without first-pass metabolism.

Any of the selected drugs identified above can be oo* conveniently administered nasally to warm-blooded animals to elicit the desired systemic, therapeutic antihistaminic antinausea or antienetic response by formulating it into a nasal o dosage form which may contain therapeuticAlly effective amounts of other physiologically active ingredients such as a decongestant, an analgesic or a bronchodilator comprising the o2 desired drug, in a systemic, therapeutically effective antihistaminic, antinausea or antiemetic amount, together with a nontoxic pharmaceutically acceptable nasal carrier therefor. As indicated earlier, the drug can be employed in the form of the free base or in the form of a pharmaceutically acceptable salt.

Suitable nontoxic pharmaceutically acceptable nasal carriers will 14 0 04 4 0 0 00 0. 4 06-00 4~ 0 go 04 4 44 4 ItO 0 too 00400

I

be apparent to those skilled in the art of nasal pharmaceutical formulations. For those not skilled in the art, reference is made to the text entitled "REMINGTON'S PHARMACEUTICAL SCIENCES", 17th edition, 1985. Obviously, the choice of suitable carriers will depend on the exact nature of the particular nasal dosage form required, whether the drug is to be formulated into a nasal solution (for use as drops or as a spray), a nasal suspension, a nasal ointment, a nasal gel or another nasal form.

Preferred nasal dosage forms are solutions, suspensions and gels, which normally contain a major amount of water (preferably purified water) in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters a base S such as NaOH), emulsifiers or dispersing agents, buffering S agents, preservatives, wetting agents and jelling agents methylcellulose) may also be present.

Most preferably, the nasal composition is isotonic, it has the same osmotic pressure as blood and lacrimal fluid, If desired, sustained release nasal compositions, sustained release gels, or when a more highly insoluble form is desired, a 20 long chain carboxylic acid salt of the desired drugs can be conveniently employed. The carboxylic acid portion of the salt preferably contains 10 to 20 carbon atoms. Such salts stearates, palmitates, etc.) can be readily synthesized, for example, by dissolving the hydrochloride salt of the drugs in water, then adding the alkali metal salt of the desired long chain carboxylic acid sodium stearate). The corresponding long chain carboxylic acid salt which precipitates out of solution is removed by filtration. Alternatively, equimolar amounts of the drug free base and the long chain carboxylic acid are combined .n methanol. That mixture is then added to a small volume of water, causing the desired salt drug stearate) to precipitate.

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15 Those skilled in the art will be aware that a systemic, therapeutically effective antinausea or antiemetic amount of a particular agent will vary with the particular agent, the age, size, weight and general physical condition of the patient.

Typically the dosage level will be more similar to the expected dosage level for intravenous administration than to the dosage levels currently employed for other methods of administration, for example oral, rectal or subcutaneous.

As a practical matter the selected therapeutic compositions will normally be prepared in dosage unit forms to contain systemic, therapeutically effective amounts of the selected antihistaminic, antinausea or antiemetic agent. In specific instances fractions of the dosage units or multiple dosage units *oo ~will be employed. Typically dosage units may be prepared to 0 4 deliver 5mg to 75mg of therapeutic agent per 0.1 to 0.4 cc of 0 0 solution or gel.

The desired isotonicity of the compositions of this ,o invention may be accomplished using sodium chloride, or other 0 pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic o solutes. Sodium chloride is preferred particularly for buffers containing sodium ions.

Viscosity of the compositions may be maintained at the a*o selected level using a pharmaceutically acceptable thickening agent. Methyl cellulose is preferred because it is readily and economically available and is easy to work with. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickener will depend upon the agent selected. The important point is to use an 16 amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.

8 8) 8 8 8048 8 081 8 8 88 8" 8 8 8g 8) 8 8 2C 8 8418888 8 8 88P 8 8 841 8 841 Preferred compositions within the scope of this .invention will contain a humectant to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of pharmaceutically acceptable humectants can be employed including, for example sorbitol, propylene glycol or glycerol. As with the thickeners, the concentration will vary with the selected agent, although the presence or absence of these agents, or their concentration is not an essential feature of the. invention.

Enhanced absorption across the nasal membrane can be accomplished employing a therapeutically acceptable surfactant.

Typically useful surfactants for these therapeutic compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides such as Tween 80, Polyoxyl 40 Stearate, Polyoxyethylene 50 Stearate and Octoxynol. The usual concentration is from 1% to 10% based on the total weight.

A pharmaceutically acceptable preservative is generally employed to increase the shelf life of the compositions. Benzyl alcohol is suitable, although a variety of preservatives including, for example, Parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed. A suitable concentration of the preservative will be from 0.02% to 2% based on the 'total weight, although there may be appreciable variation depending upon the agent selected.

Those skilled in the art will recognize that the components of the compositions must be selected to be chemically inert with respect to the active agent. This will present no problem to 17 those skilled in chemical and pharmaceutical principles, or problems can be readily avoided by reference to standard texts or by simple exprriments.

The therapeutically -effective compositions of this invention are prepared by mixing the ingredients following general.y accepted procedures. For example the selected components may be simply mixed in a blender, or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to 'control pH or an additional solute to control tonicity. Generally the pH will be S from about 3 to 7.5, although with some agents of the irvention other hydrogen ion concentrations may be selected.

0 4 44 j 00 4 0 4 The following examples are given hy way of illustration only and are not to be considered lirritations of thi invention many apparent variations of which are possible wkihout departing from the spirit or scope thereof.

o "0n 444 0 o 4 0 004* 4 00 4 4 4 0 44 18 i EXAMPLE 1 The following compositions are prepared as illustrative aqueous solutions of the named drugs suitable for use as nasal drops of nasal spray. In each case, the pH of the final composition is adjusted to 7.4 with NaOH. The solutions are adjusted to isotonicity with NaCL.

Ingredient Amount o 0 COMPOSITION A diphenhydramine 500 mg 0 "Tween 80 100 mg methylcellulose 200 mg o o water, purified q.s. 10 ml S. Final concentration 10 mg/0.2 cc a COMPOSITION B dimenhydrinate 2500 mg o 1 o Tween 80 100 mg methylcellulose 200 mg water, purified q.s. 10 ml Final concentration 50 mg/0.2 cc 19 COMPOSITION C metoclopramide 500 mg Tween 80 200 mg methylcellulose 200 mg water, purified q.s. 10 ml Final concentration 10 mg/0.2 cc EXAMPLE 2 Two Sprague-Dawley male rats each weighing 250 to 300 grams, anesthetized using sodium pentobarbital (50 mg/Kg of body weight), were administered nasally by micropipet a dosage level S of 15 mg /Kg of body weight of the following composition: a 216 mg metoclopramide'HCL (MCP'HCL) 992 mg 6.5% Tween 80 in Saline «895.2 mg polyethylene glycol (PEG 400) 522.2 mg polyethylene glycol (PEG 3350) t f 74.6 mg stearyl alcohol The femoral artery was cannulated with heparinized polyethylene tubing (Clay Adams, PE-50) and blood samples were 4 removed at the times indi .ted in Table 1.

Q

The samples were analyzed by high pressure liquid chromatography (HPLC) as follows: 20 S! Column: Silica Column (4.6 x 250 mm) Detection: 308 nm Mobile Phase: CH 2 C 2: MeOH:NH OH 90:10:0.5 Flow Rate: 1.7 ml/min.

Plasma (0.3ml) was placed in a test tube and 0.1 ml of 1'N- NaOH was added. Four ml of methylene chloride was then added and the mixture shaken for 10 minutes on a reciprocal shaker, centrifuged for 3 minutes in an IEC clinical centri2uge and the upper layer removed by aspiration. A 3.0 ml aliquot of the methylene chloride layer was transferred to a second tube and evaporated to dryness with a stream of nitrogen gas. The resulting residue was then dissolved in 0.1 to 0.5 ml of mobile e phase and submitted to HPLC analysis.

o 02 4 a0 -2 0.o 21 i The results are shown in Table 1.

TABLE 1 Nasal Absorption 0

IQ

Time Concentration* (min) (ug/mi plasma) 0 0 0.96 Q.12 10 1 '41 i- 0.10 1 .61 0. 23 1 .55 0.18 45 1 .30 0.18 60 1 .26 0.3 1.11 0.34 1 .04 0.35 120 1.10 0.38 180 1 .09 0.36 240 0.94 *Mean S.D. (nr:3) 0 a 00 4 a It will be, noted tha't the, concentration is measurable after only 5 minutes, reaches maximum concentration in 15 minutes and sustains a high levnil for at least 4 hours.

22 EXAM4PLE 3 The procedure of Example 2 was repeated with three rats except that the MCP*HCL was administered at the same dosage 1ev in isotonic sodium chloride. The results are shown in Table 2.

TABLE 2 .Nasal Absorption (Solution saline) Time Concentration* (Min) (ug/mi plasma) 4 444444 4 0 4 44 44 4 4040 4441 4 4440 4 44 44 4 444 4

I

444440 4 1 44 4 04 4 44 44 4 4 44 4444 4 4444 4 44444* 4 4 04 4 4 .4 4 44 0 5 10 15 30 75 90 120Q 150 240 0.42 0.68 0.85 1 .37 1 .51 1 .61 1 .6~2 1 .63 1 .55 1 55 1 .29 0 0 0.10 0.12 0.21 0.18 0.05 0.17 0. 18 0.26 0.21 0.28 *Ma SiD. (n±t3) 23 7 t I 0~ t .y 0 9S

OTO

99 6 i0 9 0 9 Q 0 KS 0 09a 9 e 0 oS 0 9 ts 0a It will be observed that zhS time to achieve maximum levels was extended, but that the high levels were maintained for a longer period of time.

EXAMPLE 4 A female beagle dog weighing about 10 Kg was anesthetized with sodium pentobarbital (30 mg/kg of body weight).

The following composition was administered to the nasal cavity using a syringe at a dose of 10 mg of M4CP: mg of MCP 200 mg of 5% Tween 430 mg of PEG 400 280 mg of PEG 3350 mg of stearyl alcohol A catheter was inserted into the cubital vein and the blood samples were collected at the indicated times shown in the following Table 3.

The samples were analyzed by HPLC as follows: HPLC Analysit 09 0 99 4 Column Detection Mobile Phase Flow Rate Silica column (Altex 4.6 x 250 mm) 308 nm

CH

2 C2.:MeOHI:NH 4 OH 90:10:0.5 1.7 ml/min.

24 Plasma (2.0 ml) was placed in a test tube and 0.5 ml of 1 N NaOH was added. Seven ml of methylene chloride was then added and the mixture was shaken for 10 minutes on a reciprocal shaker centrigufed at 2000 rpm for 3 minutes, and the upper layer was removed by aspiration.

A 6.0 ml alxquot of the methylene chloride was transferred to a second tube and evaporated to dryness with a stream of nitrogen gas. The resulting residue was then dissolved in 0.4 m of mobile phase and submitted to HPLC analysis.

TABLE 3 Nasal-Absorption 9 0 290 Time Concentration (min) ng/ml plasma) 0 0 5 48.1 62.5 15 78.6 90.5 112.7 i102.8 120 84.2 180 82.0 240 72.2 300 56.9 360 53.1 25

I

EXAMPLE The procedure of Example 4 was repeated except that the MCP*HCL was administered at the sa-ma dosage level in isotonic sodium chloride. The results are shown in Table 4.

TABLE 4 0*4411 44 404

S

$44 I 44 I I 04$ I 444,5, o 0 04 44 4 '0 04 00 0 *0 4 00 Nasal Absorption (Solution-Saline) Time Concentration (ngq/mJ plasma) 0 0 5 74.4 10 98.9 15 150.8 1 62.8 1 03.6 90.5 120 68.2 180 60.8 240 49.1 300 38.4 360 34.2 0 0 00 ~4 0 0 00 4 0 44 0 04 1 26

I

EXAMPLE 6 Seven Wistar rats weighing from 250 to 275 gm (Charles River Laboratories, Inc., Wilmington, MA) were anesthetized with mg/kg i.p. sodium pentobarbital. The neck was surgically opened, and a polyethylene tube (PE 260, Intramedic Clay Adams) was inserted into the trachea and tied in place. Another PE tube was inserted into the esophagus to the posterior of the nasal cavity and also secured. The juglar veins were exposed and the nasopalatine was closed with glue (Super Glue, Woodhill Permetex, Cleveland, OH). Meclizine dihydrochloride at a concentration of 6.4 mg/ml in normal saline containing 2% Tween 80 was injected at dosage levels of 0.64 mg/rat and 1.28 mg/rat by syringe through the tube into the nasal cavity. Blood (0.2 0.3 ml) was sampled at various times from the juglar veins, alternating left and S' right, and stored on ice in preheparinized microfuge tubes.

Extraction of meclizine from whole blood was performed by the method of Hom and Ebert. J. Pharm. Sci. 66: 710 (1977).

Briefly, whole heparinized blood was centrifuged on a Beckman o Microfuge B, and 0.1 ml of plasma collected. One normal HCL (0.4 ml) was added to this in another microfuge tube, and the mixture was vortexed for 30 seconds. One ml of chloroform was then added, the samples vortexed for an additional minute, and then centrifuged ngain. The entire chloroform phase was removed, Stransferred to a test tube, and evaporated to dryness with a Buchler Evapomix. The extract was resuspended in 0.2 ml of HPLC solvent and duplicate samples were injected into the HPLC for analysis.

JFor HPLC a Waters Corp., Milford, MA, system was utilized.

This consisted of models 720 B WISP autosampler, both 480 Lamda Max variable and 440 dual-channel UV detectors, 660 solvent programmer, 730 data module, M6000A and M-45 pumps, and a 3.9 x 150mm Novapak C8 column (51/m particle size) preceded by a 3.9 x 27 2 ,23 mm Corasil (particle size, 30-381im) C 18filled guard column.

The conditions for H-PLC were isocratic 23:77 0.114 sodium acetate (PH 4.3) methanol, flow rate 1.0 mi/mmn and detection at 232 nm.

The results of the analysis are shown in Table TABLE Nasal-Asbc ption 0 0 0 6 .0 0 0 04 0 Time Concentration (min) (ng/m. plasma) 0.64 1.28 Dosage Dosage 2 70 210 4 250 720 6 300 960 8 630 1100 620 970 440 720 250 530 230 210 190 340 120 110 150 100 180 180 210 70 120 240 28 EXAMPLE 7 TOXICITY STUDIES IN RABBITS A group of twenty rabbits were divided into 14 tests and 6 control animals. The test animals were administered 20 mg of metoclopramide hydrochloride in the following gel composition: 0 0 n.0 Formulation to make 100 ml at 100 mg/cc o o BENZYL ALCOHOL N.F. 1.500 ml SODIUM CHLORIDE 0.800 grams 0 a METHOCEL 4000 U.S.P. 2.000 grams ACETIC ACID N.F. 0.320 grams o00 SODIUM ACETATE U.S.P. 0.077 grams S, SORBITOL SOLUTION U.S.P. 5.000 ml 0 METOCLOPRAMIDE HCL 10.000 grams WATER PURIFIED U.S.P. q.s. 100.000 ml by nasal instillation at 8, 12 and 16 hours for a total of fourteen days. The control animals were similarly treated with isotonic saline solution.

Animals administered the metoclopramide gel formulation gained weight over the 14 days of the test period. No significant clinical observations were noted among the test animals, and treated nostrils appeared normal at all times, as compared to the untreated nostrils. Similar results were found among animals receiving the saline control solution.

29 Histopathological examination of the nasal cavities of animals sacrificed at 24 hours, 7 days and 14 days after initiation of the test, revealed no lesions which could be attributed to treatment with the test formulation. Nasal mucosal inflammation and exudate accumulation were no greater than normal background findings, and rhinitis was not higher than anticipated in conventional rabbits. Hemorrhage or blood present in the nasal cavity way considered postmortum hemorrhage. Other lesions were considered normal background lesions, not directly attributed to the test formulation.

STwo animals died on test. The death of one rabbit from the o control group was attributed to mucoid enteropathy, a common S malady in laboratory rabbits. The death of the rabbit from the test group was tentatively attributed to intussusception, not an a uncommon finding in rabbits. There was no evidence for an association between the administration of the test formulation and the death of this animal.

,0 Examination of the nasal cavities from rabbits administered the formulation containing metoclopramide revealed no lesions which could be attributed to treatment with the test composition.

The treated nasal cavities were not significantly different from untreated reference nasal cavities, or from those treated with ouo.o the saline control.

EXAMPLE 8 A 4-way crossover study was conducted in eight volunteer i human subjects to compare the effects of the nasal administration of 5 and 10 mg of metoclopramide hydrochloride in a gel formulation, 10 mg of the same agent in an oral formulation and mg of the product intramuscularly. The nasal formulation had the following composition: 30 Formulation to make 100 ml at 100 mq/cc BENZYL ALCOHOL N.F. 1.500 ml SODIUM CHLORIDE U.S.P. 0.800 grams METHOCEL 4000 U.S.P. 2.000 grams ACETIC ACID, N.F. 0.320 grams SODIUM ACETATE U.S.P. 0.077 grams SORBITOL SOLUTION U.S.P. 5.000 ml METOCLOPRAMIDE HCL 5.000 grams WATER PURIFIED U.S.P. q.s. 100.000 ml 4 i4 LQ. The oral and intramuscular compositions were commercial 4 S formulations available from A.G. Robbins Pharmaceutical Company, Richmond, under the name Reglan.

4 Substantially equivalent maximum blood levels were achieved with the 10 mg nasal, 10 mg P.O. and 5 mg I.M. The pharmacokinetic profiles for these doses were statistically identical. No evidence of local toxicity was observed during or after the study.

.1,3,444'.' 4, 4 4 0 8 31 N _I The results are shown in the following table: TABLE 6 COMPARISON OF PEAK PLASMA CONCENTRATIONS, TIME TO PEAK AND ELIMINATION RATE CONSTANTS (Kel) FOLLOWING THE ADMINISTRATION OF METOCLOPRAMIDE HCL ORALLY (PO) INTRAMUSCULARLY (IM) JMG, AND INTRANASALLY (IN) AND 10MG IN HUMAN SUBJECTS (n=8) 44; 0 00 4.44 4 4 0 04 00 4 0 00 o oo 00 0 0 Peak Concn.

(ng/ml) Time to Peak (min.) K (X10 3

PO

36.0(7.8) 97.5(21.2) 1.89(1.13)

IM

34.0(3.3) 91.9(39.6) 2.67(1 .00)

SIN

15.2(5.4) 80.6(36.7) 2.59(1 .41 1 OIN 35.1 (7.6) 131.3(39.1) 2.77(1 .26) 0 0L f 04 4a 0 04 f The study was extended to dosage levels of 20 mg and 40 mg by the intranasal route using the same compositions. Useful blood levels were achieved. There was no evidence of either local or systemic toxicity in the human subjects either before or after completion of the study.

32 EXAMPLE 9 H.F. was a 55 year-old female with Stage IV ovarian cancer.

The patient failed conventional chemotherapy and developed a complete bowel obstruction secondary to tumor growth in February, 1985.

Because of repeated nausea and vomiting due to bowel obstruction and other factors, intranasal metoclopramide at 40 mg per dose every four hours was employed for control of symptoms.

S, The intranasal metoclopramide contained her nausea between occasional bouts of vomiting which were inevitable secondary to %o the mechanical bowel obstruction. The patient had previously not S responded to antiemetic suppositories given for nausea, The formulation of the gel compositions was the same as in Example 7.

uao The study was extended to five more cancer patients who were

U

previously refractory to other antinausea treatments with the o" same formulation and same dosage schedule. All patients benefited from the treatment and four preferred this route of administration over intravenous injections.

U o 1; j 33

Claims (18)

1. A method of eliciting a systemic, therapeutic antihistaminic, antinausea or antiemetic response in a mammal which compg.ses administering nasally to said mammal a systemically, therapeutically effective anti- histaminic, antinausea or antiemetic amount of a therapeutic agent which is selected from the group consisting of cimetidine, ranitidine, terfenadine, diphenylhydramine, carbinoxamine, clemastine, phenytoloxamine, doxylamine, dimenhydrinate, tripelennamine, pyrilamine, pheniramine, chlorpheniramine, brompheniramine, dexchlorpheniramine, triprolidine, promethazine, trimeprazine, propiomazine, methdilazine, cyproheptidine, azatidine, diphenylpyraline, phenindamine, hydroxyzine, cyclizine, chlorcyclizine, buclizine, meclizine, trimethobenzamide, benzquinamide, metoclopramide, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable nasal composition.

2. The method as in claim 1 wherein the antihistamine is a meclizine. O U, 3. The method as in claim 1 wherein the antihistL:3ine is metoclopramide. 1

4. The method as in claim 1 wherein the antihistamine is S terfenadine.

5. The method as in claim 1 wherein the antihistamine is cimetidine.

6. The method as in claim 1 wherein the antihistamine is ranitldine.

7. The method as in claim 1 wherein the therapeutic agent is an antlemetic agent selected from the group consisting of meclizines, trimethobenzamide, benzquinamide, diphenhydramine, dimenhydrinate and S promethazine.

8. The method as in any one of claims 1 to 7 wherein the S pharmaceutically acceptable salt is a salt of a carboxylic acid containing from about 10 to 20 carbon atoms.

9. The method as in any one of claims 1 to 8 wherein the S 9 I pharmaceutically acceptable nasal composition is an isotonic aqueous buffer with a pH of from about 3 to 7. The method as in any one of claims 1 to 8 wherein the pharmaceutically acceptable nasal composition is an isotonic aqueous buffer with a pH of from about 3 to 7.5 containing a sufficient amount of a therapeutically acceptable thickening agent so that the viscosity is from about 2500 to 6500 cps.

11. A pharmaceutically acceptable composition suitable for nasal z-T administration and for absorption essentially through the nasal mucosa to L rk 2 35 i !I 'I i- i. a I obtain a systemic therapeutic antihistaminic, antinausea or antiemetic response in a mammal which comprises a therapeutic agent which is selected from the group consisting of cimetidlne, ranitidne, terfenadine, diphenylhydramine, carbinoxamine, clemastine, phenytoloxamine, doxylamlne, dimenhydrinate, tripelennamine, pyrilamine, pheniramlne, chlorpheniramine, brompheniramine, dexchlorpheniramine, triprolidine, promethazine, trimeprazlne, proplomazine, methdllazlne, cyproheptidine, azatidine, diphenylpyraline, phenindamine, hydroxyzine, cyclizine, chlorcyclizine, buclizine, meclizlne, trimethobenzamide, benzquinamide, metoclopramide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier, diluent, excipient and/or adjuvant,

12. The composition as in claim 11 wherein the antihistamine is a meclizine.

13. The composition as in claim 11 wherein the antihistamine is metoclopramide.

14. The composition as in claim 11 wherein the antihistamine is a cimetidine. O 15. The composition as in claim 11 wherein the antihistamine is a ran1tldlne. So° 16, The composition as in claim 11 wherein the antihistamine is terfenadine.

17. The composition as in any one of claims 11 to 16 wherein the therapeutic agent is an antiemetic agent selected from the group consisting of meclizines, trimethobenzamide, benzquinamide, diphenylhydramine, dimenhydrinate and promethazine. oo 18. The composition as in any one of claims 11 to 17 wherein the pharraceutlcally acceptable salt Is a salt of a carboxylic acid containing Sfrom about 10 to 20 carbon atoms.

19. The composition as in any one of claims 11 to 18 wherein the pharmaceutically acceptable carrier is an isotonic aqueous buffer with a pH 4* of from about 3 to 7.

20. The composition as in any one of claims 11 to 18 wherein the pharmaceutically acceptable carrier is an isotonic aqueous buffer with a pH of from about 3 to 7 containing a sufficient amount of a therapeutically acceptable thickening agent so that the viscosity Is from about 2500 to 6500 cps.

21. The composition as in any one of claims 11 to 20 in dosage unit form. TM 779V) SN ft I ~iue-~ 36

22. A pharmaceutically acceptable composition suitable for nasal administration and for absorption essentially through the nasal mucosa to obtain a systemic, therapeutic antihistaminic, antinausea or antlemetid response in a mammal, substantially as hereinbefore described with reference to any one of the Examples.

23. A method of eliciting a systemic, therapeutic antihistaminic, antinausea or antiemetic response in a mammal, substantially as hereinbefore described with reference to any one of Examples 2 to 9. DATED this FIFTEENTH day of FEBRUARY 1990 Nastech Pharmaceutical Company, Inc. Patent Attorneys for the Applicant SPRUSON FERGUSON 4I 4 Ie 0 0 ,c 00 0 0O 0 0 00 00 0 8 TMS/79v~