NOUVELLE FORME SALINE PHARMACEUTIQUE

NOVEL PHARMACEUTICAL SALT FORM

Abrégé français

L'invention concerne un sel de saccharinate de bases organiques médicinales qui ne sont pas des alcaloïdes, et constituant une nouvelle forme saline présentant des propriétés organoleptiques améliorées et une solubilité réduite.

Abrégé anglais

The saccharinate salt of synthetic non-alkaloidal medicinal organic bases
provides a novel salt form possessing improved organoleptic properties as well
as reduced solubility.

Revendications

7
Claims
1. The saccharinate salt of non-alkaloidal organic medicinal bases
capable of acid addition salt formation.
2. The salt of claim 1 wherein the base is a useful non-alkaloidal orally-
active drug selected from the group consisting of psychopharmacologics,
analgesics, neurologics, anesthetics, respiratory agents, cardiovascular-renal
agents, hematologic agents, endocrine and metabolic agents,
gastrointestinal agents, dermatologic agents, antiinflammatories,
antiallergics, immunologics, oncolytics, and antiinfectives.
3. The salt of claim 2 wherein the base is a useful orally-active
antiinfective agent.
4. The salt of claim 2 wherein the base is a useful orally-active analgesic
agent.
5. The salt of claim 2 wherein the base is a useful orally-active
cardiovascular-renal agent.
6. The salt of claim 2 wherein the base is a useful orally-active
gastrointestinal agent.
7. The salt of claim 2 wherein the base is a useful orally-active
neurologic agent.
8. The salt of claim 2 wherein the base is a useful orally-active
psychopharmacologic agent.
9. The psychopharmacologic agent of claim 8 that is useful in
depression.
10. The psychopharmacologic agent of claim 8 that is useful in anxiety.
11. The psychopharmacologic agent of claim 10 that is an azapirone.

8
12. The azapirone of claim 11 selected from buspirone and gepirone.
13. The azapirone of claim 11 is buspirone saccharinate.
14. The method of producing a saccharinate salt comprising the mixing of
a solution of an acid addition salt of the medicinal base with a solution of
sodium saccharinate.

Description

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NOVEL PHARMACEUTICAL SALT FORM
Cross Reference to Related Application
This application claims priority from provisional application
USSN 60/098,154 filed August 27, 1998.
5 Background of the Invention
The present invention relates to a novel salt form of certain
pharmacologically active organic bases and their preparation. The class will
be exemplified by the saccharinate salt of buspirone, a useful anti-anxiety
agent.
10 It is known that while many organic bases function as useful
pharmacologic agents, nonetheless salt forms are often pharmaceutically
preferred for reasons of enhanced solubility, ease of compounding, and
stability. It is also well accepted that oral dosing of drugs is a preferred
route
of administration. However, most organic bases possess a very bitter taste
15 which, for acceptable oral administration, requires masking by various
methods familiar to pharmaceutical formulation practitioners such as the
incorporation of sweeteners, flavorings, organoleptic enhancers, and the like.
The intense bitter taste of most bases can be relieved somewhat by
substituting a salt form of the pharmacologically active agent for the base in
20 pharmaceutical formulations; e.g., the hydrochloride salt. Some salt forms
of
drugs are more effective than others in reducing the objectionable taste of
the pharmaceutical formulation. It is known that patient compliance in
adhering to a drug regimen is negatively affected by pharmaceutical products
that are objectionable in taste, particularly in instances where the patient
25 disorder is accompanied by loss of appetite, nausea, and vomiting.
In U.S. 4,362,730, Rader, et al. disclosed and claimed the
saccharinate salt of vincamine, a pharmaceutically active alkaloid.
Vincamine saccharinate was described as having improved solubility and
taste characteristics. Greater solubility for the saccharinate salt of
vincamine
30 differs from the reduced solubility seen for the saccharinates of the
present
convention.

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The present invention concerns a novel salt form of non-alkaloidal
medicinal organic bases that renders the normally bitter-tasting drug much
more palatable, thereby facilitating its pharmaceutical formulation for oral
routes of administration where taste comes into play; such as liquid
5 suspensions, lozenges, chewable tablets, chewing gums, and the like.
When applied to synthetic organic base medicinals, as opposed to alkaloids,
solubility of the salt is generally less than for more standard pharmaceutical
salts such as halides, sulfates, and the like.
Detailed Description of the Invention
10 The saccharinate salt of certain non-allkaloidal organic bases provides
novel salt forms demonstrating improved organoleptic properties. For certain
medicinals the saccharinate salt also provides a means of sustaining drug
release by virtue of decreased aqueous solubility of the saccharinate
compared to more standard pharmaceutical salts such as halides, sulfates,
15 phosphates, and the like. The saccharinate salts are conveniently
synthesized by salt interchange on admixture of solutions of sodium
saccharinate and acid addition salts; e.g., the hydrochloride salt, of
medicinal
organic bases. Other salt-forming reactions, well-known to one skilled in the
pharmaceutical sciences, may also be employed.
20 Various classes of orally-active non-alkaloidal synthetic medicinal
organic bases are intended applications of the present invention. Some of
these medicinal bases fall into the following medical use categories:
~ antiinfectives such as erythromycin;
~ oncolytics;
25 ~ analgesics such as codeine, meperidine, pentazocine,
butorphanol, buprenorphine;
~ psychopharmacologics;
~ neurologics;
~ anesthetics;

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~ respiratory agents;
~ cardiovascularslcardio-renal agents
~ endocrine agents;
~ metabolic agents;
~ gastrointestinal agents;
~ antiallergenics; and
~ immunologics.
Psychopharmalogics can be subclassed as:
~ anxiolytics; e.g., benzodiazepines such as alprazolam, azapirones
such as buspirone;
~ antipsychotics; e.g., phenothiazines such as chlorpramazine and
thioridazine, piperazines such as fluphenazine, thioxanthenes such
as thiothixene, butyrophenones such as haloperidol,
dibenzoxapines such as loxapine, dihydroindolones such as
molindone; and
~ affective disorder agents such as imipramine, trazodone,
nefazodone, fluoxetine, sertraline, and the like,
dextroamphetamine and methylphenidate.
Neurologics can be represented by procyclidine, biperiden,
20 amantadine and selegiline; ergotamines and methylsergide; scopolamine,
cyclizine, hydroxyzine and the like.
Anesthetics are represented by benzocaine, dibucaine, lidocaine,
procaine and the like.

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Respiratory agents are represented by epinephrine, phenylephrine,
phenylpropanolamine and pseudoephedrine; isoproterenol and terbutaline.
Cardiovasculars can be subclassed as:
~ inotropics such as dobutamine;
5 ~ antiarrhythmics such as acecainide, disopipramide;
~ ~3-blockers such as propranolol, atenolol, nadolol;
~ calcium blockers such as diltiazem, nifedipine and nimodipine;
~ vasodilators such as papaverine and isoxsuprine;
~ antihypertensives such as hydralazine; and
10 ~ diuretics such as triamterene and amiloride.
Endocrine agents such as bromocryptine and clomiphene; and
metabolic agents such as phenformin.
Gastrointestinal agents such as metaclopramide or cimetidine.
The present invention involves stable crystalline saccharinate salts of
15 orally administrable medicinal bases. Saccharin, chemically 1,2-
benzisothiazol-3(2H)-one 1,1,dioxide, is used as a sweetener, most r
commonly in the form of its sodium salt dihydrate. While it is used as a
sweetener in pharmaceutical applications, its use is as a component of a
mixture of ingredients. While saccharine provides a sweet taste in dilute
20 aqueous solutions where it is about 500 times sweeter than sugar with the
sweet taste still detectable in 1:100,000 dilution; nonetheless saccharin has
a
bitter, metallic aftertaste. Because saccharin's taste is most pleasant in
dilute solution, care must be exercised in formulating saccharin in its solid
state because of a very objectionable taste.
25 By contrast the current invention relates to actual salt forms, as
opposed to mixtures, comprising the organic base cation and the

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saccharinate anion. In this form the medicinal has pleasant organoieptic
properties even in its solid form. As such, the saccharinate salts offer the
potential for pharmaceutical formulations without requiring large amounts of
other organoleptic enhancers such as sweeteners, flavors, and the like which
5 are usually required to render medicinal bases palatable. The advantages of
saccharinate salts would especially be evident in formulating oral
suspensions, chewable tablets, lozenges, and quick-melt dosage forms.
Another aspect of the present invention relates to the general
reduction in solubility of the saccharinate salts of the non-alkaloidal
medicinal
10 bases compared to more common acid addition salts of the medicinal bases
such as hydrohalide, sulfate, phosphate salts and the like. With reduced
solubility drug release is slowed and extended release of the drug usually
occurs. Therefore, the saccharinate salts offer a method for providing
extended release dosing for certain medicinals.
15 The present invention is illustrated by the following examples but is
not limited to them.
Example 1 - Buspirone Saccharinate
Buspirone hydrochloride (8-4[4-(2-pyrimidinyl)-1-piperazinyl])butyl]-8-
azaspiro[4.5]decane-7,9-dione hydrochloride 4.22 g, 10 mmole) dissolved in
20 a minimal amount of water was added to a concentrated solution of sodium
saccharinate (2.05 g, 10 mmole) with stirring. The mixture was chilled and
the supernatant aqueous layer decanted from the heavier oil layer which was
dissolved in methylene chloride. The methylene chloride solution was
washed with water and then dried (MgSO,). The dried solution was filtered
25 and concentrated in vacuo to a clear oil. Trituration in ether provided a
pale
yellow saccharinate salt, m.p. 142-145 °C.
Analysis:
Calculated for CZ, H3,N502~C,HSN03S: C, 59.14; H, 6.38; N, 14.78; S,
5.64.
30 Found: C, 59.14; H, 6.46; N, 14.89; S, 5.51.

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Example 2 - Taste Preference Testing
Under single-blind conditions, three small glass plates were set out for
taste-testing. Plate #1 contained buspirone hydrochloride. Plate #2
contained buspirone saccharinate, and Plate #3 contained 1:1 molar
5 equivalent amounts of buspirone hydrochloride and sodium saccharinate in
the form of a physical mixture. Tasting volunteers were asked to taste each
of the samples and give their preference. All volunteers selected Plate #2
(buspirone saccharinate) as the best tasting sample. By contrast, both
Plates #1 and #3 were labeled as objectionable to highly objectionable in
10 taste by the volunteers.