United States_ Patent Office
`
`3,636,200
`Patented Jan. 18, 1972
`
`1
`
`3,636,200
`PHARMACEUTICAL SUSPENSION
`Margaret Rose Zentner, Montclair, N.J., assignor to
`Hoffmann-La Roche Inc., Nntiey, N.J.
`No Drawing. Filed June 9, 1969, Ser. No. 831,721
`Int. CI. A61k 27106
`U.S. CI. 424-154
`
`9 Claims
`
`ABSTRACT OF THE DISCLOSURE
`Palatable, stable, thixotropic pharmaceutical suspen(cid:173)
`sions with desirable viscosity, suspendability, and reversi(cid:173)
`ble gel-sol-gel forming flow properties consisting of an
`active ingredient comprising in combination (a) a reac(cid:173)
`tion product of a therapeutically active drug substance
`which is otherwise bitter tasting because it is weakly basic
`and which contains a secondary or tertiary nitrogen in
`combination with a complex magnesium aluminum silicate
`and (b) a product consisting essentially of microcrystal(cid:173)
`line cellulose containing from about 8 to about 12% by
`weight sodium carboxymethylcellulose, are disclosed.
`
`2
`clearly superior in such desirable properties as viscosity
`and suspendability and surprisingly exhibits excellent thix(cid:173)
`otropy. Thixotropy may be defined as the property of
`a suspension to undergo reversible gel-sol-gel formation.
`5 The excellent thixotropy of the suspensions of the present
`invention is unexpected as, although the microcrystalline
`cellulose containing 8 to 12 percent by weight sodium car(cid:173)
`boxymethylcellulose exhibits a degree of thixotropy, the
`reaction products of therapeutically active benzodiaze-
`10 pines and complex magnesium aluminum silicates do not
`exhibit the property. As a result of the excellent thix(cid:173)
`otropy possessed by the suspensions of the instant inven(cid:173)
`tion, they exhibit only a minimal sedimentation; even at
`relatively low concentrations, of the benzodiazepine-com-
`15 plex magnesium alumim.im silicate reaction product, e.g.,
`about two percent weight to volume and below.
`The reason for the greatly improved flow properties
`and viscosity of the suspensions of the present invention
`is not clear. It can be speculated, however, that those re-
`20 active sites on the complex magnesium aluminum silicate
`which are not reacted with the weakly basic therapeutic
`compound are in some way reacted with the microcrys(cid:173)
`tal!ine cellulose containing 8 to 12 percent sodium car-
`boxymethylcellulose.
`In the practice of the present invention it is preferred
`to add an amount of microcrystalline cellulose contain(cid:173)
`ing, in combination, 8 to 12 percent by weight sodium
`carboxymethyl-cellulose equal to from about 0.5 to about
`4.0 times the weight of the therapeutic compound-com-
`30 plex magnesium aluminum silicate reaction product pres(cid:173)
`ent in the suspension. In the most preferred embodiments
`approximately equal amounts of each are utilized.
`In the practice of the present invention the preferred
`complex magnesium aluminum silicate is a standard arti-
`35 cle of commerce marketed by the R. T. Vanderbilt Com(cid:173)
`pany, Inc., New York, New York, under the trademark
`"Veegum." The chemical analysis of Veegum, expressed
`as oxides, is as follows:
`
`25
`
`BACKGROUND OF THE INVENTION
`It has been demonstrated that certain secondary or ter(cid:173)
`tiary nitrogen containing therapeutic substances, which
`are weakly basic in reaction, for example, certain thera(cid:173)
`peutically active benzodiazepines, may be formulated into
`essentially tasteless reaction products with certain complex
`magnesium aluminum silicates. The resulting tasteless re(cid:173)
`action products form stable suspensions in pharmaceu(cid:173)
`tically acceptable liquid vehicles which, in therapeutic
`value, compare favorably with suspensions containing the
`same concentration of therapeutically active substance and
`conventional suspending agents. It has been found, how(cid:173)
`ever, that suspensions containing relatively low concen(cid:173)
`trations, e.g., two percent weight to volume and below,
`of the reaction products of therapeutically active sub(cid:173)
`stances and complex magnesium aluminum silicates, ex- 40
`hibit an undesirably low sedimentation volume not present
`in suspensions containing higher concentrations, e.g., five
`percent weight to volume and above. The undesirable sedi(cid:173)
`mentation volume required that additional amounts of
`complex magnesium aluminum silicates or conventional 45
`agents such as natural or synthetic gums such as, for ex(cid:173)
`ample, tragacanth or clays such as bentonite had to be
`added to the drug complex magnesium aluminum silicate
`tasteless reaction product in order to achieve an acceptable
`suspension.
`
`BRIEF SUMMARY OF THE INVENTION
`The present invention comprises a method of forming
`improved suspensions containing relatively low concentra(cid:173)
`tions of the reaction product of complex magnesium alu(cid:173)
`minum silicate and a therapeutically active, weakly basic
`compound by the addition thereto of microcrystalline cel(cid:173)
`lulose which contains, in combination, about 8 to 12 per(cid:173)
`cent by weight sodium carboxymethylcellulose.
`
`DETAILED DESCRIPTION OF THE INVENTION
`This invention is predicated on the discovery that the
`flow properties of an aqueous suspension containing the
`reaction product of a weakly basic, therapeutically active
`compound and a complex magnesium aluminum silicate
`may be, unexpectedly, markedly improved by the addi(cid:173)
`tion thereto of microcrystalline cellulose which contains,
`in combination, about 8 to 12 percent by weight sodium
`carboxymethylcellulose in an amount equal to from about
`0.5 to 4.0 times the amount of the complex magnesium
`aluminum silicate present. The resulting suspension is
`
`70
`
`. Percent
`Silicon dioxide ------------------------------- 61.l
`Magnesium oxide ---------------------------- 13.7
`Aluminum oxide -----------------------------
`9.3
`Titanium dioxide ----------------------------
`0.1
`Ferric oxide ---------------------------------
`0.9
`Calcium oxide -------------------------------
`2.7
`Sodium oxide -------------------------------
`2.9
`Potassium oxide -----------------------------
`0.3
`Carbon dioxide ------------------------------
`1.8
`Water of combination -------------------------
`7.2
`
`50
`
`In another preferred embodiment of the invention a
`complex magnesium aluminum silicate sold as "Neutral
`Veegum" is employed. Neutral Veegum, like the regular
`grade of Veegum, is a standard item of commerce
`55 marketed by the American Viscose Corporation, Marcus
`Veegum differs from the regular grade of Veegum in that
`its sodium content, expressed as sodium oxide, is about
`1.0 percent. The regular grade of Veegum has a sodium
`content, expressed as sodium oxide, of about 2.9 percent.
`60 Neutral Veegum has an acid demand of less than 1 cc.
`of N/10 hydrochloric acid per gram, whereas the acid
`demand of the regular grade of Veegum is about 6 to 8
`cc. of NI 10 hydrochloric acid per gram.
`It should be fully understood that, while the present in-
`65 vention will be described with particular reference to the
`use of Veegum-type products as the complex magnesium
`aluminum silicate reactant, the underlying principle of
`the invention is applicable equally to the use of other
`complex magnesium aluminum silicate compounds which
`are similar in nature and properties to Veegum-type
`products.
`Exhibit 1152
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`3,636,200
`
`3
`The preferred embodiment of the present invention
`encompasses the utilization of a water dispersible cellulosic
`colloid which is microcrystalline cellulose containing, in
`combination, about 8 to 12 percent sodium carboxy(cid:173)
`methylcellulose as a dispersion aid. Such a product is 5
`marketed by the American Viscose Corporation, Marcus
`Hook, Pa., under the trade name "Avicel-RC." It is to be
`understood, however, that any commercially available
`microcrystalline cellulose preparation having substantially
`similar characteristics can be utilized in the practice of 10
`the present invention.
`The therapeutically active compounds which form sub(cid:173)
`stantially tasteless reaction products with the complex
`magnesium aluminum silicate in accordance with the pres(cid:173)
`ent invention are those weakly basic drugs which contain 15
`a secondary or tertiary nitrogen atom in their structure.
`Specific examples of these therapeutic agents, which are
`all extremely bitter substances in a pure form, include
`7-chloro-1-methyl-5-phenyl-3H-l,4-benzodiazepin-
`2(1H)-one;
`7-chloro-2;,3-dihydro-1-methyl-5•phenyl-1H-1,4-
`benzodiazepine;
`7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepin-
`4-oxide;
`4-(2-dimethylaminoethoxy )-N-( 3,4,5-trimethoxy(cid:173)
`benzoyl) benzylamine;
`d-3-methoxy-N-methylmorphinan;
`d-1-tropic acid ester of 3-diethylamino-2,2-dimethyl-1-
`propanol;
`2-chloro-9-( 3-dimethylaminopropylidene) thioxanthene;
`1-( 4-chlorophenethyl )-2-methyl-6, 7-dimethoxy-1,2,3,4-
`tetrahydroisoquinoline
`
`20
`
`30
`
`4
`dried and pulverized for storage or it may be utilized
`without isolation from the reaction media to form the
`improved suspensions of the present invention.
`The improved suspensions of the present invention are
`formed by conventional methods long established in the
`art of pharmaceutical compounding. The suspensions may
`contain any of the conventional adjunct materials em(cid:173)
`ployed in formulating the suspensions of the prior art.
`For example, the improved suspensions according to the
`present invention can contain preservatives such as benzoic
`acid, methyl-p-hydroxybenzoate, propyl-p-hydroxybenzo-
`ate, sorbic acid and the like; buffers such as lactic acid,
`citric acid .and the like; sweetening agents such as sugars
`or artificial sweeteners; antifoaming agents; certified color(cid:173)
`ing agents; natural and artificial flavoring agents and the
`like.
`To illustrate the superior nature of the suspensions of
`the present invention, the following suspensions were pre(cid:173)
`pared:
`(I) A suspension was prepared containing 2.44 per-
`cent weight to volume of the reaction product of diazepam
`(7 - chloro - 1,3 - dihydro - 1 - methyl - 5-phenyl-2H(cid:173)
`l,4-benzodiazepin-2-one) and complex magnesium alumi(cid:173)
`num silicate in an aqueous syrup vehicle. The suspension
`25 was not viscous and possessed pseudoplastic flow proper(cid:173)
`ties and no thixotropy. The sedimentation volume, after
`storage in undisturbed bottles for 30 days, was approxi(cid:173)
`mately 84 percent. After 120 days, the sedimentation
`volume became 55 percent.
`(Il) A suspension was prepared in a similar vehicle
`utilizing 2.0 percent weight to volume microcrystalline
`cellulose containing 8 to 12 percent by weight sodium
`carboxymethylcellulose. The suspension was initially of
`low viscosity. Upon aging, the viscosity increased some(cid:173)
`what and thixotropy was evident. There was, however, only
`slight gel formation.
`(III) A similar suspension was prepared utilizing 2.4
`percent weight to volume complex magnesium aluminum
`silicate. This suspension had a low viscosity, was only
`slightly thixotropic and did not form a gel.
`(IV) A suspension was prepared in an analogous
`manner utilizing 2.44 percent weight to volume of the
`reaction product of diazepam and complex magnesium
`aluminum silicate and 2.0 percent weight to volume
`microcrystalline cellulose containing 8 to 12 percent by
`weight sodium carboxymethylcellulose. The suspension
`possessed a relatively high viscosity, even on initial forma(cid:173)
`tion and exhibited very pronounced thixotropy. Samples
`of this suspension packed in conventional shipping con-
`tainers and driven 1700 miles in a commercial type
`shipping vehicle maintained their gel structure and showed
`no or very little sedimentation, e.g., 94--100 percent after
`120 days.
`The average apparent viscosity of 5 day old samples of
`each of the above suspensions at 0.3 r.p.m. is shown in
`Table I. A Brookfield L VT model, spindle No. 3 was
`utilized in all tests. The temperature for all tests was
`between 24° C. and 26° C. Measurements were taken in
`undisturbed four ounce amber round bottles. The bottles
`were rolled to restore homogeneity of suspension in those
`instances where sedimentation had occurred.
`
`and the like and their medicinally acceptable acid ad(cid:173)
`dition salts such as, for example, the hydrochloride salt, 35
`the hydrobromide salt or the phosphate.
`The ratio of complex magnesium aluminum silicate to
`bitter-tasting drug utilized in producing the tasteless re(cid:173)
`action products described above has been found to be
`0
`variable within rather wide limits. The ratio will, for 4
`the most part, depend upon the properties and charac(cid:173)
`teristics of the particular drug being treated. However,
`it has been established that a ratio of at least one gram
`of the complex magnesium aluminum silicate, described
`herein, for each 0.01 millimole of the drug present will 45
`produce products having completely satisfactory proper(cid:173)
`ties. In many instances, substantially lesser quantities of
`the complex silicate can be used without adversely alter-
`ing the desired properties of the final product. For ex(cid:173)
`ample, in the case of certain drugs, satisfactory products 50
`have been obtained by using a ratio of as little as one
`gram of complex magnesium aluminum silicate for each
`0.8 millimole of drug present. In any event, the optimum
`ratio of drug to complex silicate to be used in any par(cid:173)
`ticular instance can be determined readily by simple pre- 55
`liminary experimentation. The taste of the :final drug prep(cid:173)
`aration will serve as the indicia of whether the drug has
`been reacted with a sufficient quantity of the complex
`magnesium aluminum silicate.
`The substantially tasteless reaction products of the 60
`therapeutically active compounds and complex magnesium
`aluminum silicates are prepared basically by mixing them
`in aqueous media. The ingredients may be mixed in the
`dry form or with the therapeutic compound in solution
`and the complex magnesium aluminum silicate in dry 65
`form or as an aqueous suspension. The benzodiazepine
`compound may be dissolved in aqueous, aqueous-alcoholic
`or alcoholic medium depending on relative solubilities in
`each. For those compounds which are relatively insoluble
`in water, any water-miscible monohydroxy aliphatic al(cid:173)
`cohol may be used.
`The reaction may be carried out at room temperature
`or below or at elevated temperatures, e.g., up to about
`95° C., the preferred temperature range being from about
`25° C. to abcmt 75° C. The reaGtion product may be 75
`
`70
`•
`
`TABLE I
`
`Viscosity in cps.
`Suspension
`I -----------------------------------
`6,000
`1 2,000
`II ----------------------------------
`~000
`III ----------------------------------
`IV --------------------------------- i 32,000
`1 Suspensions containing microcrystalline cellulose with 8
`to 12 percent by weight sodium carboxymethylcellulose will
`increase somewhat in viscosity upon standing for several
`·weeks.
`The foregoing figures clearly illustrate the superiority
`in pharmaceutically desirable properties of the suspen(cid:173)
`sions of the present inventii:m, For a fuller understanding
`
`000002
`
`

`

`3,636,200
`
`6
`EXAMPLES 3 AND 4
`
`5
`of the nature and objects of this invention reference may
`be had to the following examples which are given as a
`further illustration of the invention and are not to be
`construed in a limiting sense. All parts given in the ex(cid:173)
`amples are parts by weight unless otherwise indicated.
`
`EXAMPLE 1
`
`In the manner of Example 1 suspensions were formu(cid:173)
`lated utilizing reaction products comprising 0.2 gram
`5 4 - (2 - dimethylaminoethoxy)-N-(3,4,5-trimethoxyben(cid:173)
`zoyl) benzylamine hydrochloride and 0.85 gram Neutral
`Veegum; and 0.2 gram 2 - chloro - 9-(3-dimethylamino(cid:173)
`propylidene)thioxanthene hydrochloride and 9.85 gram
`Neutral Veegum, respectively.
`
`10
`
`EXAMPLE 5
`
`An adsorbate of diazepam and Neutral Veegum was
`initially prepared as follows:
`1.05 grams of diazepam, a bitter tasting drug, was
`added to and dissolved in a mixture of 30.0 cc. of ethyl
`alcohol and 20.0 cc. of distilled water at a temperature of
`about 50° C. The solution while still warm was added to
`and mixed with 60.0 grams of Neutral Veegum. A small
`additional quantity of similar ethyl alcohol-water mixture 15
`was added subsequently to insure complete and thorough
`wetting of the mixture. The mixture was then stirred for a
`period of 30 minutes. Thereafter, the product was dried
`to constant weight at a temperature of 45 ° C., following 20
`which the dry powdery product was pulverized.
`24.42 grams of the product produced in the preceding
`paragraph and 20.0 grams of Avicel-RC (microcrystal(cid:173)
`line cellulose containing 8 to 12 percent sodium carboxy(cid:173)
`methylcellulose) were formulated into an aqueous sus- 25
`pension in the following manner:
`The diazepam-Veegum product was dispersed in 220
`distilled water at 90° C. which contained 0.9 gram
`methyl-p-hydroxybenzoate and 0.2 gram propyl-p-hy(cid:173)
`droxybenzoate. The dispersion was thoroughly mixed for 30
`about 10 minutes after which the Avicel-RC was added
`and the whole thoroughly stirred. 125.0 grams glycerin and
`143.0 grams sorbitol were added and the dispersion was
`cooled to room temperature. The dispersion was then
`homogenized and 550.0 grams of sucrose were dissolved 35
`therein with slight warming. Subsequently, a solution con(cid:173)
`taining 25.0 cc. of distilled water, 1.5 grams sodium hy(cid:173)
`droxide, 2.5 grams benzoic acid, 1.0 gram sodium cycla(cid:173)
`mate, 0.1 gram sodium saccharin and 0.1 gram of di(cid:173)
`sodium EDTA was added to the dispersion. Immediately 40
`afterward, 10.0 grams of lactic acid were added and the
`dispersion was thoroughly agitated to achieve a uniform
`mixture.
`A dispersion containing 0.033 gram of Antifoam C
`(a silicone-type antifoaming agent having a silicone con(cid:173)
`tent of 30 percent manufactured and sold by Dow Corn- 45
`ing Corporation, Midland, Mich.) was prepared and
`added to the mixture described in the preceding para(cid:173)
`graph. To the mixture thus produced there was added a
`filtered solution of FD and C colors and flavoring agents
`as needed. Thereafter, the pH of the product was ad- 50
`justed to about 4.0 with sodium hydroxide. Finally, dis(cid:173)
`tilled water was added to the preparation to a volume of
`1000 cc. and the suspension was mixed, homogenized and
`deaerated.
`
`In a similar manner, a suspension was formulated
`utilizing equal amounts of Avicel-RC 101 and the powder
`obtained by grinding together in a mortar 0.31 gram
`d-3-methoxy-N-methylmorphinan hydrobromide and 1.24
`grams Veegum, granulating the mixture with 6.5 cc.
`distilled water and drying at a temperature of about
`45° c.
`What is claimed:
`1. An improved palatable pharmaceutical suspension
`with desirable viscosity, suspendability, and reversible gel(cid:173)
`sol-gel forming thixotropic flow properties comprising a
`medicinally acceptable liquid vehicle having suspended
`therein an active ingredient consisting essentially of the
`reaction product produced by mixing complex magnesium
`aluminum silicate with a therapeutically active, weakly
`basic compound characterized in that it is otherwise bitter
`tasting because it contains in its structure a secondary or
`tertiary nitrogen in combination with a product consisting
`essentially of microcrystalline cellulose and from l!Jbout
`8 to about 12% by weight sodium carboxymethylcellulose
`said product being present in from about 0.5 to about 4.0
`times the weight of said complex magnesium aluminum
`silicate present in said suspension.
`2. The improved pharmaceutical suspension in ac(cid:173)
`cordance with claim 1 wherein said therapeutically active
`weakly basic compound is selected from the group con-
`sisting of 4 -
`(2 - dimethylaminoethoxy)-N-(3,4,5-tri(cid:173)
`methoxybenzyl) benzylamine and salts thereof with a
`medicinally acceptable acid.
`3. The improved pharmaceutical suspension in accord(cid:173)
`ance with claim 1 wherein said therapeutically active
`weakly basic compound is selected from the group con(cid:173)
`sisting of d-3-methoxy-N-methylmorphinan and salts
`thereof with a medicinally acceptable acid.
`4. The improved pharmaceutical suspension in accord(cid:173)
`ance with claim 1 wherein said therapeutically active,
`weakly basic compound is selected from the group con-
`sisting of 2 - chloro - 9 - (3-dimethylaminop(fopylidine)
`thioxanthene and salts thereof with a medicinally accepta(cid:173)
`ble acid.
`5. The improved pharmaceutical suspension in accord(cid:173)
`ance with claim 1 wherein said therapeutically active,
`weakly basic compound is a benzodiazepine compound.
`6. The improved pharmaceutical suspension in ac-
`cordance with claim 6 wherein said benzodiazepine com(cid:173)
`pound is diazepam.
`7. The improved pharmaceutical suspension in accord(cid:173)
`ance with claim 6 wherein said 1benzodiazepine compound
`60 is 7 - chloro - 2,3 - dihydro - 1-methyl-5-phenyl-lH-1,4-
`benzodiazepine or a salt thereof with a medicinally ac(cid:173)
`ceptable acid.
`8. The improved pharmaceutical suspension in accord(cid:173)
`ance with claim 6 wherein said benzodiazepine compound
`65 is chlordiazepoxide or a salt thereof with a medicinally ac(cid:173)
`ceptable acid.
`9. In a method of forming a pharmaceutical suspension
`by suspending a stable, palatable reaction product pro(cid:173)
`duced by mixing complex magnesium aluminum silicate
`70 with a therapeutically active, weakly basic compound
`characterized in that it is otherwise bitter tasting because
`it contains in its structure a secondary or tertiary nitrogen
`in a medicinally accepable liquid vehicle, the improve(cid:173)
`ment whereby desirable viscosity, suspendability and re-
`75 versible gel-sol-gel forming thixotropic flow properties are
`
`55
`
`EXAMPLE 2
`
`A suspension was prepared utilizing 7-chloro-2,3-di(cid:173)
`hydro - 1- methyl-5-phenyl-lH-1,4-benzodiazepine hydro(cid:173)
`chloride as the therapeutically active compound.
`In this example, 5.0 grams Neutral Veegum and 20.0
`grams Avicel-RC were dispersed in 280 cc. distilled water
`at about 80° C. To this dispersion was added amounts
`of sorbitol, glycerin and the p-hydroxybenzoate preserva(cid:173)
`tives corresponding to those utilized in Example 1 and the
`whole was homogenized. 500 grams sucrose were dis(cid:173)
`solved in the resulting aqueous dispersion with warming to
`about 40° C.
`1.05 grams of 7-chloro-2,3-dihydro-1-methyl-5-phenyl(cid:173)
`lH-l,4-benzodiazepine hydrochloride dissolved in 40.0 cc.
`distilled water were then added and the whole was
`thoroughly mixed.
`The remaining sweeteners, flavoring agents, coloring
`agents and the like shown in Example 1 were added in
`similar quantities and the final suspension was adjusted to
`1000 cc., homogenized and deaerated.
`
`000003
`
`

`

`7
`obtained which comprises suspending said reaction
`product in combination with a product consisting essenti(cid:173)
`ally of microcrystalline cellulose and from about 8 to
`;about 12% by weight sodium carboxymethylceUulose,
`said product being present in from about 0.5 to about 4.0 5
`times the weight of said complex magnesium aluminum
`silicate present in said suspension.
`
`3,636,200
`
`3,146,168
`3,248,290
`3,251,824
`3,337,402
`3,337,403
`3,347,744
`
`8
`8/1964 Battista ---------- 424-362 X
`4/1966 Zentner ---------- 424-362 X
`511966 Battista ---------- 424-362 X
`8/1967 Zentner ------------ 424-184
`8/1967 Zentner ------------ 424-184
`10/1967 Latshaw et al. ____ 424-362 X
`
`References Cited
`UNITED STATES PA TENTS
`3,060,086 10/1962 Kueter ---------- 424-260 X
`7/1964 Zentner ------------ 424-260
`3,140,978
`
`SHEP K. ROSE, Primary Examiner
`
`10
`
`U.S. Cl. X.R.
`424-155, 244, 260, 276, 357, 362
`
`000004
`
`