CA2101189C - Agglomerated hydrophilic complexes with multi-phasic release characteristics - Google Patents

Agglomerated hydrophilic complexes with multi-phasic release characteristics

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Publication number
CA2101189C
CA2101189C CA002101189A CA2101189A CA2101189C CA 2101189 C CA2101189 C CA 2101189C CA 002101189 A CA002101189 A CA 002101189A CA 2101189 A CA2101189 A CA 2101189A CA 2101189 C CA2101189 C CA 2101189C
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CA
Canada
Prior art keywords
gum
surfactant
dosage form
esters
solid dosage
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA002101189A
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French (fr)
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CA2101189A1 (en
Inventor
Anand R. Baichwal
John N. Staniforth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Penwest Pharmaceuticals Co
Original Assignee
Mendell Edward Co Inc
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Publication of CA2101189A1 publication Critical patent/CA2101189A1/en
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Publication of CA2101189C publication Critical patent/CA2101189C/en
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin

Abstract

The present invention relates to a controlled release formulation which includes a therapeutically active medicament, a heterodisperse gum matrix, a pharmaceutically acceptable diluent, and an effective amount of a pharmaceutically acceptable surfactant and/or wetting agent to provide a multi-phasic controlled release of a therapeutically active medicament. The invention also relates to a method of preparing the same.

Description

~G(a7GOP31EI3~.T~I7 hiX'IJIZO~HI~TC ~flM~~E~LH~
WITH FItJJ~TT-1H~SI~: FtE7~EPiSH C:Ht'~Ite~.~°aT~;FtIL~TIC~
The advantages of rorutrolled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increas-ing patient compliance by reducing the number of adminis-trations necessary to achieve tkie same. These advantages have been attained by a wide variety of methods.
For examp3.e, different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi°synthetic or of natural origin. ~ few contain both synthetic and non°synthetic material. ~iowever, some of the systems require special process and production equipment, and in addition some of 'these systems are susceptible to variable drug release.
Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements.
For the most part, the release rate of oral delivery systems have been classified according to the mechanism of release, such as zero order, first order, second order, pseudo-first order, etc., although many pharma--ceutical compounds release medicament via other, complicated mechanisms.
First order mechanisms refer to situations where the reaction rate is dependent on the concentration of the reacting substance (and therefore is dependent on the first power of the reactant). In such mechanisms, the substance decomposes directly into one or more products.
Second order mechanisms occur when the experiment°
ally determined rate of reaction is proportional to the \/ C
~;_;_~~.~'>z~
concentration of each of 'two reactants, or 'to the second power of the concentratian of one reactant.
Pseudo first order reactions are genera7.ly defined as second order reactions which behave as 'though 'they are governed by a first order mechanism, and occur, for example, when the amount of one reacting material is manipulated by being present in great excess or being maintained at a constant concentration as compared to the other substance. In such circumstances, the reaction rate is determined by the manipulated substance.
Zero order mechanisms refer to si'tua'tions where 'the reaction rate is independent of the concentration of 'the reacting substance (and therefore is dependent on the zer~ power of the reactant), the limiting factor being something other than the concentration of the reacting substance (e.g., the medicament). The limiting factor in a zero order mechanism may be, for example, the solubility of the reacting substance or the light intensity in photochemical reactions.
As previously mentianed, however, many chemical reactions are not simple reactions of zero-, first-, or second-order, etc., and instead comprise a combination of two or more reactions.
Moreover, other factors may influence 'the reaction rate, including temperature, pI-I, food effect variability, ions and ionic strength dependency, viscosity dependency, corrosion/ erosion variability, content uniformity problems, flow and weight uniformity problems, carrying capacity and mechanical strength problems, hydrolysis, 3t3 photochemical decompasition, interaction between components (such as interactions between the drug and other ingredients in the formulation, such as buffers, preservatives, ete.), the concentration of solvents of low dielectric constant (when 'the reaction involves oppositely charged ions) , e~tc.
Generally, controlled release pharmaceutical formulations wh.icln provide zero order release characteristics have been considered most desirable because such a mechanism would theoretically provide constant drug levels. This is based on the assumption that the rate of elimination is determinative of the release rate of the medicament from the formulation, rather than the rate of absorption, etc.
~Iowever, for medicaments which are not very soluble in the stomach and where absorption is desired for a prolonged period of time, a bimodal release mechanism is considered to be desirable.
Bimodal or multi-phasic release is characterized by an initial high rate followed by a slower rate as the dosage form passes the upper portion of the small intestine where absorption is maximum and finally another higher rate as the dosage form passes into the further end of the intestine where absorption is less than before.
Bimodal release is considered to be advantageous for a number of reasons, including but not limited to the fact that bimodal release allows the formulator to com-pensate for changing absorption rates of the medicament in the gastrointestinal tract by providing a rapid onset of action (when the formulation is located in the stomach) and compensate for relatively slow absorption by providing a relatively rapid release rate (e.g., cahen the formulation is located in 'the large intestine).
Bimodal release formulations have been provided in a i 30 number of different manners to date.
,, 'For example, International Publication Number WO/87/00044 describes therapeutic formulations including certain hydroxypropylmethylcellulose which are said to have bimodal release characteristics) ~1 ~~ ~_ ~ ~. ..rL c~ ~

See also, A.C. Shah et al., °°Gel-Matrix Systems Exhibiting Bimodal Controlled Release For Oral Drug Delivery°', Journal of Controlled Release, 9(1989), pp.
169--175, which also reports that certain °'types" of hydroxypropylmethylcellulose ethers are found to display a bimodal drug release profile. P. Giunchedi et al., °°Ketoprofen Pulsatile Absorption From °Multiple Unit' Hydrophilic Matrices°', International .Journal of Pharma-ceutics, 77{1991), pp. 177-181 described an extended release oral formulation of Ketoprofen comprising a multiple unit formulation constituted by four hydrophilic matrices of identical composition, each containing 50 mg of drug and prepared with hydroxypropylmethylcellulose (Methocel~) and placed in a gelatin capsule. Pulsatile plasma levels (2 peaks at 2nd and 8th hours after dosing) were said to be obtained, whereas in vitro tests resulted in a fairly constant drug release. U. Conte et al. , ''A
New Ibuprofen Pulsed Release Oral Dosage Form'°, Drug Development And Industrial Pharmacy, 15(14-16), pp.
2583-2596 (1989) reported that a pulsed released pattern was obtained from a 3-layer tablet wherein two layers contained a dose of drug, and an intermediate layer acted as a control element (a mixture of hydroxypropylmethyl-celluloses) separating the drug layers. K. A. Kahn et al, °°Pharmaceutical Aspects And In-Vivo Performance Of Brufen Retard - An Ibuprofen BR Matrix Tablet", Proced.
Intern. Symp. Control. Rel. Bioact. Mater., 18(1991), Controlled Release Society, Inc., describes a formulation containing 800 mg of ibuprofen which is said to provide a bimodal release pattern, the release retarding agent utilized therein being xanthan gum.
The Assignee's U.S. Patent Nos. 4,994,276, 5,128,143, and 5,135,757, reported that a controlled release excipient which is comprised of synergistic heterodisperse polysaccharides (e, g., a heteropoly--~~~:~~~z;

saccharide such as xanthan gum in combination with a polysaccharide gum capable of cross-linking with the heteropolysaccharide, such as locust bean gum) is capable of processing into oral solid dosage forms using either 5 direct compression, following addition of drug and lubricant powder, conventional wet granulation, or a Combination of the two. The release of the medicamewt from the formulations therein proceeded according to zero-order or first-order mechanisms.
The controlled release excipiemts disclosed in U. S.
Patent Nos. 4,994,276, 5,128,143, and 5,135,757 are commercially available under the tradename TIMERxT'" from Edward Mendell Co., Inc., Patterson, N.Y., which is the assignee of the present invention.
Tt is 'therefore an object of the present invention to provide a formulation capable of providing multi-phasic or bi-phasic controlled release of a therapeu-tically active medicament.
It is a further object of the present invention 'to provide a means of converting the mechanism of drug release provided by formulations comprising the excipient described in U.S. Patent Nos. 4,994,27&, 5,128,143, and 5,135,757 from zero-order or first-order to a bi-phasic or mufti-phasic mecharii~m.
It is a further object of the present invention to provide a controlled release mufti-phasic excipient which can be mixed with a medicament and tableted to thereby provide a mufti-phasic release of the active agent when the tablet is exposed to aqueous fluids, gastro-intestinal fluids, etc.
It is a further object of the present invention to provide a controlled release tablet which releases a therapeutically active medicament according to bi- or mufti-phasic kinetics.

~~~ a:~~ ~~~

The above-mentioned objects and others are achieved by virtue of the present a.nvention, which relates in part to a controlled release :Eormula~tion comprising a con-trolled release exc:ipient comprising a tieterodisperse polysaccharide component and a saccharide component; a further component comprising a surfactant and/or a wetting agent; and a therapeutically active medicament.
More particularly, it has now been surprisingly dis-covered that combination of pharmaceutically acceptable surfactants and/or wetting agents in the controlled re-lease excipients disclosed in U.S. Faten-t Nos. 4,994,276, 5,128,143, and 5,135,757 can be used to cause changes in release patterns and produce bi- or multi-phasic profiles of the final formulation, possibly via further changes in cross-linking, gel strength and gel-sol transitions.
The present invention further relates to a con-trolled release oral solid dosage form, comprising a heterodisperse material comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum in the presence of aqueaus solutions, the ratio of said he~teropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the ratio of said inert diluent to said heterodisperse material being from about 3:7 to about 7:3; and an effective amount of a pharmaceutically acceptable surfactant or wetting agent to provide a mufti-phasic release of a therapeutically active agent. In a preferred embodiment, the formulation of the present invention comprises a tablet.
The present invention further relates to a method for preparing an oral. solid dose formulation providing a mufti-phasic release of a therapeutically active medica-:35 ment when said dosage form i.s exposed to aqueous or ', , .. ~ . . : : .. ; . . , , ,. , . . :. ..; . , , , ~ , , . '. . .
~: .
; ,,:

. .. ,~i. n:' v,'.

i= ' ' . ' ' ~

., ,, . . . .
" ' , f ;" . . ~ . . ..~. , . , . .:

gastric fluid. In the method, a heteropolysaccharide gum is mixed with a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum in the presence of aqueous solutions, such that 'the ratio of said hetero-polysaccharide gum to said homopolysaccharide gum is from about 1:3 to about 3:1, to Obtain a heterodisperse gum matrix. ~n inert pharmaceutical diluent is added to said heterodisperse gum matrix such that the ratio of the inert diluent 'to said heterodisperse gum matrix is from about 3:7 to about 7:3.
An effective amount of a medicament is added to render a therapeutic effect. ~n effective amount of a pharmaceutically acceptable surfactant or wetting agent is added to provide a mufti-phasic release of said medicament when 'the dosage farm is exposed to aqueous fluid.
The presewt invention is further related to a con-trolled release mufti-phasic pharmaceutical excipient comprising a heterodisperse gum matrix comprising a heteropolysaccharide gum and a homopolysaccharicle gum capable of cross-linking the heteropolysaccharide gum in the presence of aqueous solutions, an inert pharmaceu-tical dlluent selected from the group consisting of mono-saccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, and from about l to about 20 percent by weight of a pharmaceutically acceptable surfactant or wetting agent. The ratio of heteropolysaccharide gum to homopolysaccharide gum, as ,cell as the ratio of inert diluent to heterodisperse gum matrix in the controlled release mufti-phasic ~xcipient is as set forth above with respect to the final formulation.
The present invention further relates to a method for preparing a controlled release dosage form which exhibits mufti-phasic release of a medicament incorpor-ated therein, comprising preparing a controlled release ..._ '.J t ~ ~ ~ ~ ~ '/y '~

mufti-phasic excipient as described above, and :incorpor-ating a therapeutically effective amount of a medicament along with any pharmaceutically necessary additives such as a lubricant, and tableting the mixture.
The following drawings are illustrative of embodi-ments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
Fig. 1 is a graphical representation of the dissolution curve (expressed as percent dissolved over time) provided by the tablets of Example 2 (no surfactant);
Figs. 2-9 are clraphical representations of the dissolution curves (expressed as percent dissolved over time) provided by the tablets of Examples 3-10 (surfactant(s) included);
Fig. 10 is a graphical representation of the dis-solution curve (expressed as release rate over time) provided by the tablets of Example 2 (no surfactawt);
Figs. 11-18 are graphical representations of the dissolution curves (expressed as release rate over 'time) provided by the tablets of Examples 3-10 (surfactamt(s) included).
' The term "heteropolysaccharide" as used in the i present invention is defined as a water-soluble ..., polysaccharide containing twa or more kinds of sugar vunits, 'the heteropolysaccharide having a branched or helical configuration, and having excellent water-wicking 't properties and immense thickening properties. When admixed with an appropriate homopolysaccharide gum capable of cross-linking with the heteropolysaccharide in accordance with the present invention and exposed to an aqueous solution, gastric fluid, etc., the gums pack v,;
~? closely and many intermolecular attachments are formed .::!
which make the structure strong and provide a hydrophi:Lic :; 35 gum matrix having high gel strength.

9 93-352, Xanthan gum, the preferred heteropolysaccharide, is produced by microorganisms, for instance, by fermentation with the organism xanthomonas compestris. l~3ost preferred is xanthan gum which is a high molecular weight ~>1U6) heteropolysaccharide.
Other preferred heteropolysaccharides include deriv-atives of xanthan gum, such as deacylated xanthan gum, the carboxymethyl ether, and the propylene glycol ester.
The homopolysaccharide gums used in the present invention which are capable of cross-linking with. the heteropolysaccharide include the galactomannans, i.e., polysaccharides which are composed solely of mannose and galactose.
A possible mechanism for the interaction between the galactomannan and the heteropolysaccharide involves the interaction between the helical regions of the heteropoly-saccharide and the unsubstituted mannose regions of the galactomannan. Galactomannans which have higher propor-°
tions of unsubstituted mannose regions have been found to achieve more interaction with the heteropolysaccharide.
Hence, locust bean gum, which has a higher ratio of mannose to the galactose, is especially preferred as compared to other galactomannans such as guar and hydroxypropyl guar.
The inert filler of the excipient preferably comprises a pharmaceutically acceptable saccharicle, including a monosaccharide, a disaccharide, and/or mixtures thereof. Examples of suitable inert pharma-ceutical fillers include sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, mixtures thereof and the like. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be used.
The excipient of the present invention has uniform packing characteristics over a range of different ~'~6~~1 particle size distributions and is capable of processing into tablets using either direct compression, following addition bf drug and lubricant powder or conventional wet granulation.
5 The properties and characteristics of a specific excipient system prepared according to the present in-vention is dependent in part on the individual character-istics of the homo and hetero polysaccharide constitu-ents, in terms of polymer solubility, glass transition 10 temperatures etc., as well as on the synergism both between different homo and heteropolysaccharides and between the homo and heteropolysaccharides and the inert saccharide constituents) in modifyincJ dissolution fluid-excipient interactions.
A homodisperse system of a heteropolysaccharide typically produces a highly ordered, helical or double helical molecular conformation which provides high :-; viscosity without gel formation. In contrast, a homo-disperse system of a homopolysaccharide typically is only 5 20 slowly soluble and ungelled at low temperatures. Two steps which are generally required for gelation are the fast hydration of the macromolecules which comprise the hydrodisperse polysaccharide material and thereafter the association of the molecules to form gels. These two important properties which are necessary to achieve a slow release hydrophilic matrix are maximized in 'the :#
'~ present invention by 'the particular combination of '' materials. Prolonged exposure to the dissolution fluid promotes solubilization, which allows molecules to associate and undergo gelation, and may result in inter-macromolecular cross-7.inking in ribbon or helical "smooth" regions.
The heterodisperse excipient of the present inven--tion comprises both hetero- and homo- polysaccharides which exhibit synergism. The heterapolysaccharide /i 7 ~ .~ C, ) r ,~ t.

component arts to produce a faster gelation of 'the homopolysaccharide component and the homopolysaccharide acts to c.ross~link 'the normally free he~teropolysaccharide helices. The resultant gel is faster-forming and more rigid. Heteropolysaccharides such as xanthan gum have excellent water wicking properties which provide fast hydration. On the other hand, the combination of xanthan gum with homopolysaccharide gums which are capable of cross-linking the rigic'i helical ordered structure of the xanthan gum (i.e. with unsubstituted mannose regions in the galactomannans) thereby act synergistically to pro-vide a higher than expected viscosity (i.e., high gel strength) of the matrix. The combination of xamthan gum with locust bean gum with or without the other homopoly-saccharide gums is especially preferred. However, 'the combination of any homopolysaccharide gums known to produce a synergistic effect when exposed to aqueous solutions may be used in accordance with the present invention. By synergistic effect, it is meant that the combination of two or more polysaccharide gums produce a higher viscosity and/or faster hydration than that which would be expected by either of the cJums alone.
:Lt is also possible that the type of synergism which is present with regard to the gum combination o:E 'the present inventa.on could also occur between -two homogen-eous or two heterapol.ysaccharides.
In the present invention, it has been discovered that the controlled release properties of the tablets are optimized when the ratio of heteropolysaccharide gum to homopolysaccharide material is about 2:1, although heteropolysaccharide gum in an amount of from about 20 to about 80 percent or more by weight of the heterodisperse polysaccharide material provides an acceptable slow release product.

r ~~.t~~~ ~~) 12 ~3-3~2 The mixed individual and synergistic viscosity madi-fyi.ng and gel-.forming characteristios of the excipierrt system of the present invention produce a variety of possible release~controlling mechanisms in any given excipient system. Some of this behavior has been ded scribed, for example, by Frisch, "Sorption and Transport in Classy Polymers -- A Review", Polymer Eng. Sci. 20 (1980), pp. 2-13, Fan & Singh, °'Controlled Releasee Quantitative Treatment", published by Springer verlag, Berlin and London (1989), pp; 111-156; and Korsmeyer et al., "Mechanisms of Solute Release .from Porous hydro-philic Polymers", Int. Vii. Pharm. 15 (1983), pp. 25-35.
The rate-limiting step for the dissolution of tab-lets of the present invention is believed to be dependent to a large extent upon the penetration of water (or gastric fluid) into the tablet to dissolve the poly-saccharides and the drug(s). It is further believed that the presence of the surfactant in the formulation allows faster initial penetration of fluid and an initial "burst" of drug release from the formulation. A second burst of drug release may then occur due to the further action of the su.rfactamt, as the fluid front from one side of the tablet meets the fluid front on the opposite side. The above hypotheses are included for discussion purposes only and are not intended to limit the scope of the present invention.
The chemistry of certain of the ingredients compris-ing the excipients of the present invention such as xanthan gum is such that the excipients are considered to be self-buffering agents which are substantially insensa.--tive to the solubility of tree medicament and likewise insensitive to the pH changes along the length of the gastrointestinal tract.
The final formulation of the present invention comprises a sufficient amount of surfactant or wetting ~_'L~)~~~t;~~

agent to provide a mufti-phasic release of the drug{s).
In certain preferred embodiments, 'the surfactant or wetting agent comprises from about 1 'to about 10 of the final formulation, by weight. ~-Iowever, the upper limit of the amount of surfactant or wetting agent included in the formulations of the present invention may be higher than 10%; the limiting concern being that the final product should provide a pharmaceutically acceptable formulation. For example, in the case of tablets, 'the upper lim it of the amount of surfactant or wetting agent included is determined by the production of a pharma-ceutically acceptable tablet, e.g., a tablet which has a friability of less than about 1~ and a hardness of 6-8 kg.
la The surfactants which may be used in the present invention generally include pharmaceutically acceptable anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphophilic) surfactants, and non-ionic surfactants. Suitable pharmaceutically acceptable anionic surfactants include, for example, monovalent alkyl carboxylates, acyl lactyla-tes, alkyl ether carboxylates, D7-acyl sarcosinates, polyvalent alkyl carbonates, ~1-acyl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, alkyl sulfates (in°
cluding sodium lauryl sulfate (SLS)), ethoxylated alkyl sulfates, ester linked sulfonates (including docusate sodium or dioctyl sodium succinate (17SS)), alpha olefin sulfonates, and phosphated ethoxylated alcohols.
Suitable pharmaceutically acceptable cationic surfactants include, for example, monoalkyl quaternary ammonium salts, dialkyl quaternary ammonium campounds, amidoamines, and aminimides.
suitable pharmaceutically acceptable amphoteric (amphipathic/amphophilic) surfactants, include, for ~s~~~~3 1~ 93-352 example, N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, and N-alkyl ~-aminoproprionates.
Suitable pharmaceutically acceptable wetting (solu-bilizing) agents, include pharmaceutically acceptable IlOn-ionl.C surfactants such as, .for example, polyoxyethyl-ene compounds, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxyl-ated alcohols, ethoxylated/ propoxylated block polymers, and propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, sorbitan esters, sucrose esters, and glucose (dextrose) esters.
Other suitable pharmaceutically acceptable wetting (solubilizing) agents include acacia, benzalkonium chloride, cholesterol, emulsifying wax, docusate sodium, glyceryl monostearate, lanolin alcohols, lecithin, polox-amer, poloxyethylene castor oil derivatives, poloxyethyl-ene sorbitan fatty acid esters, poloxyethylene stearates, sodium lauryl sulfates, sorbitan esters, stearic acid, and triethanolamine.
Mixed surfactant/wetting agent systems are also useful in conjunction with the present invention.
Examples of such mixed systems include, for example, sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid.
The change in the mechanism of drug release from the excipients of the present invention from mono-phasic to bi- or mufti-phasic release may further be altered or enhanced by process changes during the manufacture of 'the excipient, or by formulation alteration. Further modifi-cations in bi- or mufti-phasic release profiles can be effected by addition of synergism-modifying components.
For example, this can occur as a result of selection of ~. ~. e?
i5 93°352 interacting polysaccharides in which the synergism is potentiated by ionic strength of pH. In addition, the saccharide component may alsa be changed, although 'the effect of different saccharides on drug release is much smaller than that of different polysaccharides, but may still be important in achieving fine control of drug release. The dissolution profiles of a tablet formula-tion containing an excipient system with a given hetero-disperse polysaccharide component can also be modified by alteration of the ratios of heteropolysaccharide to homopolysaccharide. Alternatively or additionally, the drug release profiles can also be controlled by changing the ratio of heterodisperse polysaccharides to saccha-rides in the excipient system.
velays in the onset of mono or multi-phasic release, which may be desirable in order to optimize colonic absorption, can be produced through changes in core formulation or by application of tablet coatings to 'I further modify drug release patterns.
i In addition to the inclusion of surfactants/wet~ting agents, the drug release mechanism of the controlled release excipient of the present invention may be further manipulated by altering the process utilized :For tablet-Y
ing i.e. direct compression v/s wet granulation v/s combination of both, and via changes in the formulation i ~i itself (i.e., changes in the ratio of heterodisperse polysaccharide to insert saccharide, etc.).
An effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may be added to the abave-mentioned ingredients of the excipient be added at the 'time the medicament is added, or in any event prior to compression i into a said dosage form. Most preferred is magnesium ~tearate in any amount of about 0.5-3o by weight of the solid dosage form.

The combination of the heterodisperse polysaccharide material (i.e., a mixture of xanthan gum and locust bean gum) with the inert saccharide diluent provides a ready--to--use product in which a formulator need only blend 'the desired active medicament and an optional lubricant with the exc.ipient and then compress the mixture to form slow release tablets. The excipient may comprise a physical admix of the gums along with a soluble excipient such as compressible sucrose, lactose or dextrose, althaugh it is preferred to granulate or agglomerate the gums with plain (i.e., crystalline) sucrose, lactose, dextr.~ose, e-tc., to - form an excipient. The granulate form has certain advan-tages including the fact that it can be optimized for flow and compressibilityo it can be -tableted, formulated in a capsule, extruded and spheronized with an active medicament to form pellets, etc.
The pharmaceutical excipients prepared in accordance with the resent invention ma be p y prepared according to any agglomeration technique to yield an acceptable excipient product. Tn wet granulation techniques, 'the r desired amounts of the heterpolysaccharide gum, the ;:a homopolysaccharide gum, and the inert saccharide diluent ;;
'~! are mixed together and thereafter a moistening agent such as water, propylene glycol, glycerol, alcohol or 'the like a 25 is added to prepare a moistened mass. ~lex~t, 'the moist ened mass is dried. The dried mass is then milled with conventional equipment into granules, Therefore, the ;..a excipient product is ready to use.
The excipient is free-flowing and directly compress-ible. Accordingly, the ~xcipient may be mixed in 'the i desired proportion with a therapeutically active medica-.t ment and optional lubricant (dry granulation). Alterna-tively, all or part of the excipient may be subjected 'to a wet granulation with the active ingredient and there°
':j 35 after tableted. The complete mixture, in an amount a sufficient to make a uniform batch of tablets, is 'then subjected to tableting in a conventional production scale tableting machine at normal compression pressure, i.e.
about 2000-1600 lbs/sq in. lHowever, the mixture should not be compressed to such a degree that there is subsequent difficulty in its hydration when exposed to gastric fluid.
One of the limitations of direct compression as a method of tablet manufacture is the size of the tablet.
If the amount of active is high a pharmaceutical formu-lator may choose to wet granulate the active with other excipients to attain an acceptable tablet size with the correct compact strength. LTSUaIIy the amount of filler/
binder or excipients needed in wet granulation is less than that in direct compression since the process of wet granulation contributes to some extent toward the desired physical properties of a tablet.
The average tablet size for round tablets is prefer-ably about 500 mg to 750 mg and for capsule-shaped tab-lets about 750 mg to 1000 mg. The average particle size of the granulated excipient of the present invention ranges from about 50 microns to about 400 microns and preferably from about 185 microns to about 265 microns.
The particle size of the granulation is not narrowly critical, the important parameter being 'that the average particle size of the granules, must permit the formation of a directly compressible excipient which forms pharma-ceutically acceptable tablets. The desired tap and bulk densities of the granulation of the present invention are 3o normally between from about 0.3 to about 0.8 g/ml, with an average density of from about o.5 to about 0.7 g/ml.
For best results, the tablets formed from the granula-tions of the present invention are from about 6 to about 8 kg hardness. The average flow of the granulations pre-pared in accordance with the present invention are from .;
. , ..
, , .
' : ,' : J
. . . . ' . ..

, .;. . ~ ....~, ~ '; .', ~. . .:.. . . ..:...~ .
I ,'., . ., ' : '. .. ' '. .. . ,.
' '.. ':'.: . ~'.:'.' . '.-. ' .,..:1. .; ,: . .,.,., ,;.,., ~ .. ,.;. :
~''' '.:. .: ~::' . . ~... .' . ...~ ;..., ... ,',.
,'' ' .' . '~ ' . : ' ' ' . . . .. ' ,. . :'. . :' . ~'. ~ . ' . . , ,, . ' , . .. . ' .. . . , ' about 25 to about 40 g/sec. Tablets compacted using an instrumented rotary tablet machine have been found to possess strength profiles which are largely independent of the inert saccharide component. Scanning electron photomicrographs of largely tablet surfaces have provided qualitative evidence of extensive plastic deformation on compaction, both at the tablet surface and across the fracture surface, and also show evidence of surface pores through which initial solvent ingress and solution egress may occur.
A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e.g., pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of such therapeutically active agents include antihistamines (e. g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e. g., acetylsalicylic acid, codeine, morphine, dihydromorphone, oxycodone, etc.), anti-inflammatory agents (e. g., naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, acetysalicylic acid, sulindac), gastro-intestinals and anti-emetics (e. g., metoclopramide), anti-epileptics (e. g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e. g., codeine phosphate), anti-asthmatics (e. g. theophylline), anti-spasmodics (e. g., atropine, scopolamine) hormones (e. g., insulin, heparin), diuretics (e.g.,eltacrymic acid, bendrofluazide), anti-hypotensives (e. g., propranolol, clonidine), bronchodilators (e. g., albuterol), anti-inflammatory steroids (e. g., hydrocortisone, triamcinolone, prednisone), antibiotics (e. g.
tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, ~~ ~~~.a~

sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive.
The ratio of medicament to the heterodisperse poly-saccharide is based in part upon the relatively solubil-ity of the medicamewt and the desired rate of release.
A. computer aided pharmacokinetic model can be used 'to predict likely in vivo drug blood levels .from condition-independent in-vitro drug profiles.
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
~X.~IPL~ ~. ~Pxior A:rt~
Tablets containing appropriate amounts of propran-olol hydrochloride together with a homoclisperse poly-saccharide (lacust bean gum) and a heterodisperse polysaccharide controlled release excipient (xanthan gum/locust bean gum in a 1:1 ratio), inert pharmaceutical diluent (saccharide component), and 1% magnesium stearate are prepared either using direct compression or following wet granulation in a high speed mixer processor (Baker Perkins Ltd., Stoke on Trent, U.K.), as described in U.S.
Patent Nos. 4,994,276, 5,128,143 and 5,135,757. Tablets are compacted to approximately l4kP crushing force and in-vitro testing is carried out using an automated disso-lution apparatus and the U.S.P. paddle method with a stirring speed of 50 rev min-1. All of the dissolution studies are carried out in distilled water.
In--vitro release profiles for propranolol hydro-chloride tablets are found to have first order profiles using a homodisperse polysaccharide whereas a hetero-disperse polysaccharide excipient provides a zero order release profile.

~, ~:'~.~.
20 93°352 EX~.P~PLE 2 - F'ri~r Ar't A slow release exc.ipient is prepared by combining xanthan gum, locust bean gum, and dextrose 9.n the amounts set forth in Table 1 below, and dry blending (Baker Perkin [Machine # 5407], blender settings (chopper 1000rpm, impeller = 800 rpm)) the mixture for 2 minwtes.
Table 1 - Excipient Granulation Tnaredient o 100 Xanthan gum 25.0 225.0 Locust bean gum 25.0 225.0 Dextrose 50.0 450.0 Total 100.Oo 9008 Thereafter, water (115 ml) is added slowly and the mixture is blended for 1.5 minutes. The mixture is then dried overnight at 50°C in an oven. Next, the mixture is screened through a 20 mesh screen, with particles larger than 20 mesh being discarded.
Next, 354.5 grams of °the granulated slow release excipient and 35.5 grams of phenylpropanolamine HC1 are added into a 2 quart V-blender and blended for 10 minutes. Next, 8 grams of Lubritab~" is added, and the mixture is blended for 5 minutes. Thereafter, 2.0 grams ;.i of magnesium stearate is added and the mixture is blended far 5 minutes. Finally, the mixture is tableted to pro-~:i i 25 vide tablets of approximately 846 mg and approximately 5-7 Kp. Further information concerning Example 2 is set forth in Table 2 belaw:
:,, Table 2 - Examtale 2 Ingredient ma/tablet o 400 :.i Excipient 750.0 88.6 354.5 Phenylpropanolamine 75.0 8.9 35.5 s Lubritab 27.0 2.0 8.0 Mactnesium stearate 4.0 0.5 2.0 Total 846mg/tab 100% 4008 .;

21 93~-352 E~CAP4PT~E~ 3 - 10 In Example 3, the slow release granulation i.s pre-pared in similar .fashion to Example 2., except that after the gums and dextrose are combined, 1.30 ml of water is added, and the mixture is dried in an aeroma-tic fluid bed dryer for 45 minutes at 70°C (Type Strea-1). The ingred-ients of the slow release granulation of Example 3 are set forth in Table 3 belowo Table 3 - Excipient Granulation Ingredient % 1000c~
Xanthan gum 25.0 250.0 Locust bean gum 2,5.0 250.0 Dextrose 50.0 500.0 Total 100.Oo 1000g Thereafter, 336.4 grams of the granulated slow release excipient and 33.6 grams of phenylpropanolamine HC1 are added into a 2 quart V-blender and blended for 10 minutes. Next, 20.0 grams of surfactant (sodium lauryl sulfate) and 8 grams of lubritabT~ are added, and the mixture is blended for 5 minutes. Thereafter, 2.0 grams of magnesium stearate is added and the mixture is blended for 5 minutes. Finally, the mixture is tableted to provide tablets of approximately 892 mg and approximately 5-7 Kp. Further information concerning Example 3 is set forth in Table 4 below:
Table 4 - Example 3 Ingredient mq,~ablet % ~ 400c Excipient 750/0 84.1 336.4 Phenylpropanolamine 75.0 8.4 33.6 *Surfactant (SLS) 44.7 5.0 20.0 Lubritab 17.8 2.0 8.0 Magnesium stearate 4.5 0.5 2~0 Total 892mg/tab 100.00 4008 Examples 4-10 are prepared in on to similar fashi Example 3. In each of Examples 410,the formulations ~~n .~
~,~ ~ .x. ; ~ (7 are dry blended with a 1:5 drug:gum ratio. The percent of gum in the xanthan gum/locust bean gum/dextrose mixture in each formulation is 500. Each formulation contains 75 mg phenylpropanolamine HC1 and 75o mg of the slow release excipient granulation, and this mixture is blended in a 2 quart v-blender for 10 minutes. Then, 2% lubritab is add-ed along with the surfactant, and blended for 5 minutes.
The surfactant used is sodium lauryl sulfate and/or docu-sate sodium. Finally, 0.50 of magnesium stearate is add-ed and the mixture is blended for 5 minutes, and tableted to the specified tablet weight. The tablet weights, amount (percentage) arid type of surfactants used in Examples 3-10 are set forth in Table 5 below:

Granulation Tablet Example Surfactant" ~ Surfactant wt. ~~mg~
Ex. 3 SLS 2 863.9 Ex. 4 SLS 5 891.9 Ex. 5 SLS 10 942.9 Ex. 6 DSS 2 863.9 r Ex. 7 DSS 5 891.9 Ex. 8 DSS 20 942.9 Ex. 9 SLS + DSS 1 + 1 863.9 Ex. l0 SLS + DSS 2 + 2 882.4 "SLS refers to sodium lauryl sulfate, and DSS refers to docusate sodium.
E.CAMPLES 1~. - ~2 DISSOLUTION TESTS - PERCENT
DISSOLVED OVER TTME AND RELEASE RATE
Next, dissolution studies are conducted or the tablets of Examples 2-10 in order to determine the percent dissolved of drug over time, as well as the release rate of the drug (phenylpropanoiamine Hcl). The dissolution tests were conducted in a DI water medium having a volume of 7.000 mL by the paddle method. The . mixer rotation is 100 rpm, the height is 2.5 cm, 'the 23 93-35z temperature is 37° C, and the wavelength used is 2l0 nm.
The calibration factor is determined according to the following equation:
calibration factor = concentration of standard * 100 _ concentration o:E sample * absorbance of std The percent of the drug dissolved is then determined according to the following equation:
% active dissolved = calibration factor * absorbance of sample The dissolution and release rate data for Examples 2-10 is based on a 6 tablet dissolution study. Figs. 1-9 are graphical representations of the dissolution curves (expressed as percent dissolved over time) provided by the tablets of Example 2 (no surfactant added) and Exam--pies 3-10 (surfactant(s) included), respectively. Figs.
10-18 axe graphical representations of the dissolution curves (expressed as release rate over time) provided by the tablets of Example 2 (no surfactant added) and Examples 3-10 (surfactant(s) included). As is readily apparent from the results, 'the formulations of Examples 3-10 provide a multi-phasic release of phenylpropanol-amine HCl.

Preparation of Controlled Release Excipient For Multiphasic Dosage Forms Controlled release excipients far rnultiphasic dosage forms according to the present application are prepared as follows.
In Examples 13-14, 250 grams of xanthan gum, 250 grams of locust bean gum, 50 grams of surfactant and 450 grams of dextrose are blended for two minutes in a mixer (Baker Perkins blender), blender setting (chopper = 1,000 y 35 xpm, impeller = 800 rpm).

1, _~ lr Tn Examples :~.5-1S, 100 grams of surfactant and 400 grams of dextrose are blended with 250 grams of xanthan gum and 250 grams of locust bean gum far 'two minutes.
The surfactant in Examples 13 and 16 is sadium lauryl sulfate (SLS), while in Examples 14 and 15, the surfactant is docusa~te sodium succina~te (DSS) .
Thereafter, about 112 ml of water is slowly added 'to the mixtures and 'then blended for an additional 1.5 minutes. The mixed product, which is now a.n the form of granules, is removed from the blender and dried in an aeromatic fluid bed dryer (type: Strea--1) for 30 minutes at a temperature of 70°C. The dried granulation is 'then passed through a 20 mesh screen.
In Exatt~ples 13-14, 'the final composition of the mix-tore is 2.5.0% xanthan gum, 25.0% locust bean gum, S.Oo surfactant and 45.Oo dextrose by weight. 1n Examples 15-16, the final composition of the mixture is 25.Oo xanthan gum, 25.0% locust bean gum, 10.0% surfactant and 40.Oo dextrose by weight.
The product of Examples 13-16 is now ready to be used as a controlled release excipient for multiphasic dosage forms, and may now be admixed with one or more active ingredients and any other pharmaceutically necessary additives, and tableted.
The weight and percentages of the ingredients for the controlled release excipients used in Examples 13-16 are set forth in Tables 1215 below:

ExAMPLE 13 Ingredient ~l0ooa o Xanthan Gum 250.0 25.0 Locust Bean Gum 250.0 25.0 Surfactant (TYPE) 50.0 (SLS) 5.0 Dextrose 450.0 45.0 ~ t ~~ :~ ~ ~3 ~~

Ingredient c~~000c~ o Xanthan Gum 250.0 25.0 Locust Bean Gum 250.0 25.0 Surfactant (TYPE)50.0 (DSS) 5.0 Dextrose 450.0 45.0 Inctredient 10008 0 Xanthan Gum 250.0 25.0 Locust Bean Gum 250.0 25.0 Surfactant (TYPE)100.0 (DSS) 10.0 Dextrose 400.0 40.0 Ingredient ~oou Xanthan Gum 250:0 25.0 Locust Bean Gum 250.0 25.0 Surfactant (TYPE)100.0 (SLS) 10.0 Dextrose 400.0 40.0 TOTAL 10008 100%

y Preparation of Controlled Release Tablets :r 30 Controlled release i.ablets according to 'the presewt invention are prepared as follows.
Tn Examples 17-19, 278.43 grams of the excipient of ~Che present invention is first blended with 27.82 grams a of phenylpropanolamine HCl for 10 minwtes in a 2-quart v- , blender.

26 93°352 The excipient of Example 13 is used in Example 17, the excipient o:~ Example 14 is used in Example 18 and the exci.pient of Example 16 is used in Example 19.
After the initial blending of 'the mixtures in Exam-s pies 17-19, 7 grams of LubritabT~' and 35 grains of MCC--50i~I
are blended with each mixture for an additional 5 min-utes. Thereafter, 1.75 grams of magnesium stearate is added to 'the mixtures of Examples 17~-29, and then blended for another 5 minwtes.
Finally, the mixtures in Examples 17-19 are tableted to provide tablwts of approximately 942.8 mg and approximately 2.0 Kp.
In Examples 17-19, the final composition of the mix-ture is 79.50 excipient, 7.95% phenylpropanolamine HCl, 2.Oa Lubritab~~, 1.O.Oo MCC-50M (microcrystalline cellu-lose) and 0.5% of magnesium stearate by weight. Further information concerning Examples 17-19 axe set forth in Tables 16-18 below:
TABLE 1f Ing~rediewt m tab o 350 Excipient 750.0 79.55 278.43 PPA 750.0 7.95 27.82 Lubritab 18.85 2.00 7.00 MCC-50M 94.28 10.00 35.00 MacL_Stear. 4.71 0.50 1.75 TOTAL 942.85 1000 3508 PPA HCl = Phenylpropanolamine Hydrogen Chloride Mag. Stear. = Magnesium stearate Ingredient m tab o 350 Exc~.pient 750.0 79.55 278.43 PPA 75.0 7.95 27.82 ~. U ~ ~ !i Lubritab 18.8F 2.00 7.00 MCC-50M 94.28 10.00 35.00 Maa. Stear. 4.71 0.50 1.75 TOTAL 942.85 1000 350g PPA HCl = PhenylpropanolamineHydrogenChloride Mag. Stear. = Magnesium Stearate Ingredient m tab o c3 35U

Excipient 750.0 79.55 278.43 PPA 75.0 7.95 27.82 Lubritab 18.86 2.00 7.00 MCC-50M 94.28 10.00 35.0(3 Mach Stear. 4.71 0~5U 1.75 TOTAL 942.85 100% 3508 PPA HC1 = PhenylpropanolamineHydrogenChloride Mag. Stear. = Magnesium Stearate ,n 20 In Example 20, 292.50 grams of the excipient of , f.
Example 13 are blended with 48.75 grams of phenyl-propanolamine HC1 for 10 minutes in a 2-quart V-blender, After the initial blending, 7 grams of Lubritab'~" and 1.75 grams of magnesium stearate are added to the mixture which is then blended for another 5 minutes.
"' Finally, the mixture is tableted to provide tablets of approximately 538.46 mg and approximately 20 Kp.
Tn Example 20, 'the final composition of 'the mixture is 83.570 excipient of Example 13, 13.934 phenylpro-,'j; 30 panolamine HC1, 2.0% LubritabT"° and 0.5% magnesium i stearate by weight. Further information concerning "!' Example 20 is set forth in Table 19 below:

b j ~ i ~ '~ ~ 'l a ~ _~_ ~ ~. .~ c~ a 28 93°352 Tin r-ediemt mc~"Ltab % 350~c Excipient 450.0 83.57 292.50 PPA F-IC1 75.0 13.93 48.75 Lubritab 10.77 2.00 7.00 Mad. Stear. 2.69 0,50 7_.75 TOTAL 538.46 1000 3508 PPA HC1 = Phenylpropanolamine I-Iydrogen Chloride Mag. Stear. = Magnesium Stearate In Example 21, 487.5 grams of the excipient of Example 15 is first blended with 48.75 grams of phenyl.propanolamine IIC1 for 10 minutes in a 2-quart V-blender.
After the initial blending, 11 grams of Lubritabi"~
and 2.75 grams of magnesium steara~te is added to the mixture and blended for an additional 5 minutes.
The mixture is then tableted to provide tablets of approximately 845.15 mg and approximately 2.0 kg.
In Example 21, 'the final composition of 'the mixture is 88.64% excipient of Example 15, 8.860 phenylpro-panolamine I-ICl, 2.Oo Lubritab~ and 0.5% magnesium stearate by weight. Further information concerning Example 21 is set forth in Table 20 below:

I~rediemt mc~~b o G 350 Excipient 750.0 88.64 487.50 PPA HCl 75.0 8.86 48.75 LubritabT~ 16.92 2.00 11.00 Maq. Stear. 4.23 0.50 2.75 jy TOTAL 846.15 100% 5508 PPA HCl = Phenylpropanolamine Hydrogen Chloride ."
Mag. Stear. = Magnesium Stearate ;r c;

The examples provided above are not meant to be exclusive. Many other variations of the present invention would be obvious to 'those skilled in the art, and are contemplated to be within the scope of 'the appended claims.

Claims (30)

1. A controlled-release oral solid dosage form for absorption of an active medicament in the gastrointestinal tract, comprising:
an effective amount of a medicament to render a therapeutic is effect;
a controlled release excipient comprising a heterodisperse gum matrix comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum in the presence of aqueous solutions, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1; and an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the ratio of said inert diluent to said heterodisperse gum matrix being from about 3:7 to about 7:3; and an effective amount of a pharmaceutically acceptable surfactant or wetting agent to provide a multi-phasic release of said medicament when said dosage form is exposed to aqueous fluid.
2. A controlled release oral solid dosage form, comprising:
(i) a heterodisperse gum matrix comprising xanthan and locust bean gum in a ratio of about 1:1:

(11) an inert pharmaceutically acceptable diluent selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the ratio of said diluent to said heterodisperse gum matrix being from about 3:7 to about 7:3:
(iii) an effective amount of a medicament to render a therapeutic effect; and (iv) from about 1 to about 10 by weight of a pharmaceutically acceptable surfactant or wetting agent, said surfactant or wetting agent being selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants, and mixtures of any of the foregoing, said medicament having a multi-phasic release of said medicament when exposed to aqueous fluid.
3. The oral solid dosage form of claim 1, wherein said heteropolysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust bean gum.
4. The oral solid dosage form of claim 1, wherein said surfactant or wetting agent comprises from about 1 to about 10 percent of said formulation, by weight.
5. The oral solid dosage form of claim 1, which releases said medicament according to bi-phasic kinetics.
6. The oral solid dosage form of claim 2, which releases said medicament according to bi-phasic kinetics.
7. The oral solid dosage form of claim 1, wherein the ratio of said inert diluent to said heterodisperse gum matrix is about 1:1.
8. The oral solid dosage form of claim 2, wherein the ratio of said inert diluent to said heterodisperse gum matrix is about 1:1.
9. The oral solid dosage form of claim 1, wherein said surfactant or wetting agent is selected from the group consisting of pharmaceutically acceptable anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphophilic) surfactants, non-ionic surfactants, and mixtures of any of the foregoing.
10. The oral solid dosage form of claim 9, wherein said surfactant or wetting agent is an anionic surfactant selected from the group consisting of monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-aryl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, alkyl sulfates, ethoxylated alkyl sulfates, ester linked sulfonates, alpha olefin sulfonates, phosphated ethoxylated alcohols; a cationic surfactant selected from the group consisting of monoalkyl quaternary ammonium salts, dialkyl quaternary ammonium compounds, amido-amines, aminimides; an amphoteric surfactant selected from the group consisting of N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, N-alkyl .beta.-aminoproprionates; a non-ionic surfactant selected from the group consisting of polyoxyethylene compounds, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, sorbitan esters, sucrose esters, glucose (dextrose) esters; or mixtures of any of the foregoing.
11. The oral solid dosage form of claim 2, wherein said surfactant or wetting agent is an anionic surfactant selected from the group consisting of monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-aryl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, alkyl sulfates, ethoxylated alkyl sulfates, ester linked sulfonates, alpha olefin sulfonates, phosphated ethoxylated alcohols; a cationic surfactant selected from the group consisting of monoalkyl quaternary ammonium salts, dialkyl quaternary ammonium compounds, amido-amines, aminimides; an amphoteric surfactant selected from the group consisting of N-substituted alkyl amides, N-alkyl betaines, sulfobetaines, N-alkyl .beta.-aminoproprionates; a non-ionic surfactant selected from the group consisting of polyoxyethylene compounds, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, sorbitan esters, sucrose esters, glucose (dextrose) esters; or mixtures of any of the foregoing.
12. The oral solid dosage form of claim 1, wherein said surfactant or wetting agent is a wetting agent selected from the group consisting of acacia, benzalkonium chloride, cholesterol, emulsifying wax, docusate sodium, glyceryl monostearate, lanolin alcohols, lecithin, poloxamer, poloxyethylene castor oil derivatives, poloxyethylene sorbitan fatty acid esters, poloxyethylene stearates, sodium lauryl sulfates, sorbitan esters, stearic acid, triethanolamine, and mixtures of any of the foregoing.
13. The oral solid dosage form of claim 9, wherein said surfactant or wetting agent is selected from the group consisting of sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid.
14. The oral solid dosage form of claim 2, wherein said surfactant or wetting agent is selected from the group consisting of sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid.
15. The oral solid dosage form of claim 9, wherein said surfactant or wetting agent comprises sodium lauryl sulfate, docusate sodium, or a combination of sodium lauryl sulfate and docusate sodium.
16. The oral solid dosage form of claim 2, wherein said surfactant or wetting agent comprises sodium lauryl sulfate, docusate sodium, or a combination of sodium lauryl sulfate and docusate sodium.
17. The oral solid dosage form of claims 1-16, wherein said therapeutically active medicament is selected from the group consisting of antihistamines, analgesics, anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, anti-spasmodics, hormones, diuretics, anti-hypotensives, bronchodilators, anti-inflammatory steroids, antibiotics, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, and stimulants.
18. The oral solid dosage form of claims 1-16 which is a tablet.
19. The oral solid dosage form of claim 17 which is a tablet.
20. The use of the oral solid dosage form of claims 1-16 for oral administration to a human patient to provide a multi-phasic controlled release of a therapeutically active medicament.
21. The use of the oral solid dosage form of claim 17 for oral administration to a human patient to provide a multi-phasic controlled release of a therapeutically active medicament.
22. The use of the oral solid dosage form of claim 19 for oral administration to a human patient to provide a multi-phasic controlled release of a therapeutically active medicament.
23. A method for preparing an oral solid dose formulation providing a multi-phasic release of a therapeutically active medicament when said dosage form is exposed to aqueous or gastric fluid, comprising:
mixing a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum in the presence of aqueous solutions, such that the ratio of said heteropolysaccharide gum to said homopolysaccharide gum is from about 1:3 to about 3:1, to obtain a heterodisperse gum matrix;
adding an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, to said heterodisperse gum matrix such that the ratio of said inert diluent to said heterodisperse gum matrix is from about 3:7 to about 7:3;
adding an effective amount of a medicament to render a therapeutic effect , and adding an effective amount of a pharmaceutically acceptable surfactant or wetting agent to provide a multi-phasic release of said medicament when said dosage form is exposed to aqueous fluid.
24. A method for preparing a controlled release dosage form which exhibits multi-phasic release of a medicament incorporated therein, comprising:
preparing a controlled release multi-phasic excipient by mixing (i) a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum in the presence of aqueous solutions, such that the ratio of said heteropolysaccharide gum to said homopolysaccharide gum is from about 1:3 to about 3:1, with (ii) an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the ratio of said inert diluent to said heterodisperse gum matrix being from about 3:7 to about 7:3; and (iii) a pharmaceutically acceptable surfactant or wetting agent;
adding a therapeutically effective amount of a medicament to said controlled release multi-phasic excipient;
and compressing said mixture of controlled release multi-phasic excipient and medicament into tablets, said surfactant or wetting agent being included in an amount sufficient to provide a multi-phasic release of said medicament from said tablet when said tablet is exposed to aqueous fluids.
25. The method of claim 23, further comprising compressing the final mixture into tablets.
26. The method of claim 23 or 24, wherein from about 1 to about 10 percent by weight surfactant or wetting agent is added.
27. The method of claim 23 or 24, wherein said surfactant or wetting agent is selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants, and mixtures of any of the foregoing.
28. A controlled release multi-phasic pharmaceutical excipient, comprising:
a heterodisperse gum matrix comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of cross-linking said heteropolysaccharide gum in the presence of aqueous solutions, the ratio of said heteropolysaccharide gum to said homopolysaccharide gum being from about 1:3 to about 3:1;
an inert pharmaceutical diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof, the ratio of said inert diluent to said heterodisperse gum matrix being from about 3:7 to about 7:3; and from about 1 to about 20 percent by weight of a pharmaceutically acceptable surfactant or wetting agent.
29. The pharmaceutical excipient of claim 28, wherein said heteropolysaccharide gum comprises xanthan gum and said homopolysaccharide gum comprises locust bean gum, and said inert diluent comprises lactose, dextrose, sucrose, fructose, microcrystalline cellulose, xylitol, sorbitol or mixtures thereof.
30. The pharmaceutical excipient of claim 28, wherein said surfactant or wetting agent comprises from about 1 to about 10 percent of said formulation by weight.
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