CA2124353A1 - Sustained release composition and method utilizing xanthan gum and an active ingredient - Google Patents
Sustained release composition and method utilizing xanthan gum and an active ingredientInfo
- Publication number
- CA2124353A1 CA2124353A1 CA002124353A CA2124353A CA2124353A1 CA 2124353 A1 CA2124353 A1 CA 2124353A1 CA 002124353 A CA002124353 A CA 002124353A CA 2124353 A CA2124353 A CA 2124353A CA 2124353 A1 CA2124353 A1 CA 2124353A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- xanthan gum
- composition
- niacin
- weight
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Abstract
A compacted sustained release composition for delivering a drug as an active ingredient to the gastro-intestinal tract comprises an effective amount of the active ingredient in mixture with xanthan gum, the active ingredient comprising in excess of 40 percent by weight of the total of the active ingredient and the xanthan gum, the mixture being in the form of a unit dose in capsule or tablet form. In addition to niacin, the active ingredient may be an analgesic, antipyretic, anti-inflammatory agent, vitamin, electrolyte replenisher, decongestant, antihistamine, and useful bacteriological organisms for the gastro-intestinal tract.
Description
~-~)93/187~8 f~ 3 J 3 PCl`/US93/02804 DESCRIPTION
SUSTAINED RELEASE COMPOSITION AND METHOI:) UTILZING XANTHAN
GUM AND AN ACTIVE INGRED~ENT
5 Technical Field This invention relates to a composition and method of manufacture and use in which xanthan gum is combined with an active pharmaceutical or other ingredient in a compacted dose form for delivering the active ingredient to the gastro-intestinal tract over a sustained period.
Back~round Art Sustained or slow release compositions containing pharmaceutical medications or other active ingredients are designed to contain higher concentrations of the medicament or ingredient and are prepared in such a manner15 as to effect sustained or slow release into the gastr~intestinal digestive tract of humans or animals over an extended period of time. Well absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient regime compliance, a more ~0 sustained drug blood level response, the possibility of effecting therapeutic action with less ingested drug, and the mitigation of side effects. By providing a slow and steady release of the medicament over time, absorbed drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood,level response. ---Many therapeutic agents, medicaments, or other active ingredients have a wide window for absorption, meaning that the drug has been demonstrated to be well absorbed along the entire digest tract. Such agents, medicaments, or other active ingredients are then logical candidates for possible dosage as a sustained or slow release medication.
Sustained or slow release therapeutic dose forms are based on rnany and varied principles. For example, one of the techniques of preparation involves - formation of the drug in generally spherical pellet form wherein a specific quantity of pellets are set aside for immediate release and the remaining drug pellets orspheres are coated with various thicknesses of a suitable fat, or resinous, or fatty resinous like coating. When fractions of the pellets are blended together and then filled into capsules or pressed into tablets, without destroying the integrity of the coatings, suitable slow or sustained release dose forms may be effected. Another WO g3/18758 Pcr/US93/028o4~
SUSTAINED RELEASE COMPOSITION AND METHOI:) UTILZING XANTHAN
GUM AND AN ACTIVE INGRED~ENT
5 Technical Field This invention relates to a composition and method of manufacture and use in which xanthan gum is combined with an active pharmaceutical or other ingredient in a compacted dose form for delivering the active ingredient to the gastro-intestinal tract over a sustained period.
Back~round Art Sustained or slow release compositions containing pharmaceutical medications or other active ingredients are designed to contain higher concentrations of the medicament or ingredient and are prepared in such a manner15 as to effect sustained or slow release into the gastr~intestinal digestive tract of humans or animals over an extended period of time. Well absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient regime compliance, a more ~0 sustained drug blood level response, the possibility of effecting therapeutic action with less ingested drug, and the mitigation of side effects. By providing a slow and steady release of the medicament over time, absorbed drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood,level response. ---Many therapeutic agents, medicaments, or other active ingredients have a wide window for absorption, meaning that the drug has been demonstrated to be well absorbed along the entire digest tract. Such agents, medicaments, or other active ingredients are then logical candidates for possible dosage as a sustained or slow release medication.
Sustained or slow release therapeutic dose forms are based on rnany and varied principles. For example, one of the techniques of preparation involves - formation of the drug in generally spherical pellet form wherein a specific quantity of pellets are set aside for immediate release and the remaining drug pellets orspheres are coated with various thicknesses of a suitable fat, or resinous, or fatty resinous like coating. When fractions of the pellets are blended together and then filled into capsules or pressed into tablets, without destroying the integrity of the coatings, suitable slow or sustained release dose forms may be effected. Another WO g3/18758 Pcr/US93/028o4~
2~ 2~3a3 technique is to admix the therapeutic agent with fats and solid polyhydric alcohols, such as polyoxyethylene glycol, and/or a solid surfactant, such as polyoxyethylene glycol distearate, and press the mixture into tablets to form an erosion matrix to effect slow or sustained release dosage forms. Another method employs the use 5 of a therapeutic agent bound to an ion exchange resin or otherwise complexed with an organic or inorganic molecule and imbedded in a waxy core or granule and administered in capsule or pressed tablet form. Still another method employsthe use of an ;ndigestible film former such as methylcellulose applied to a powder or granule base containing a therapeutic agent followed by subsequent forming 10 into compressed tablek to effect slow or sustained release. Yet another method employs a tablet containing a specific drug coated with an indigestible f~lm in which the film is pierced by a laser beam to allow for a small and precise portal *om which the drug is slowly released.
As a result of the increased awareness of the importance o~
15 hypercholesterolemia and ik relationship to coronary heat disease during the last several years, there has been an in^reased emphasis on treatment with niacin (nicotinic acid). Guidelines for adults have recently been published by the National Cholffterol Education Program, coordinated by the National Heart, Lung and Blood Institute, which state that a desirable blood cholesterol level is below 5.17 20 mmol/liter. Approximately half of adults screened have been found are encouraged to see a physician for further analysis and instruction. It has been recommended that dinicians use a bile add sequesterant or niacin as first line therapy for treatment of hypercholesterolemic patients. Niacin is also the oldest of the pharmacologic agenk used in the treatment of hyperlipidemia and, since its 25 introduction in 1955, it has been in continuous use either monadically, or in combination with bile add binding resin therapy.
In doses of 3~ g/day, which exceed its requirements as a B Vitamin, niacin ~but not niacinamide) is highly effective in redudng elevated levels of plasma cholesterol and triglycerides. Niacin inhibits adipose tissue lipo!ysis, reduces30 plasma free fatty acid levels and decreases ve~ low density lipoprotein synthesis, thereby decreasing the production of low density lipoproteins from the very low density lipoproteins. Niacin is of demonstrated value in preventing manifestations of arteriosclerotic heart disease, having been shown to decrease recurrent nonfatal myocardial infarction in the coronary drug project by 40% without concurrent 35 increase in mortality from nonarteriosclerotic c~uses as has been obse~ed with clofibrate.
2 1 2 ~ ~ .J 3 ~093/187S8 PCI/US93/02804 Niacin is readily absorbed from the stomach and intestinal tract and has no difficulty passing the tissue barrier. Following per os administration of a tablet or capsule dosage of niacin peak plasma levels are obtained within 15-30 minutes inhumans. Tt e drug is rapidly distributed in the various tissues including kidney and 5 adipose tissue with a slower metabolism of liver and brown fat. Also of note is the observation that niacin has the ability to penetrate the blood brain barrier.
Niacin is rapidly eliminated from plasma and its elimination halflife in humans is 20~5 minutes. Although large doses of 3~ g/day of niacin are required to decrease circulating cholesterol and triglycerides in humans, it does not appear 10 that the high peak serum îevels attained are required, since the lipid lowering effect is maintained after plasma niadn levels are below the limit of sensitivity of the analytical method used. Thus, there is no correlation between systemic levels ofniacin and its pharmacological effect.
The chief drawback to using niacin in the treatment of hyperlipidemia is 15 hdal and truncal flushing, which occurs in nearly all users shortly after ingestion of tablets with as smaii a dosage as 75 mg of niacin per tablet~ It appears that niacin induces flushing by increasing th~ formation and/or release of some prostaglandin, which in turn increases the production of cyclic amp. However, this mechanism does not appear to mediate the effect of niacin on lipolysis. The side effects of 20 truncal flushing, nausea, gastro-intestinal upset, and rectal itching experienced following the ingestion of high potency niacin tablets~ (500 mg/tablet) has contributed to patient dropout of niacin therapy introduced to treat hyperlipidemia.
It has been difficult to produce a slow or sustained release niacin prod~ct by the conventional methods of barrier coating or erosion-type mechanisms. The 25 classic concept of a sustained release dosage regimen is to release 20-35% of the therapeutic agent within the first hour and to sustain the remaining portion of the therapeutic agent over a ~12 hour period. When one considers that the niacin therapeutic dose is 50~1000 mg and that niacin will cause a flushing response inmost subjects with a dosage release of more than 75 mg within a one hour period,30 the problem becomes apparent. Nicobid, marketed by Armour Pharmaceuticals, h~s been the most widely marketed sustained release dose form of niacin in recent y ~rs. Clinical evaluations of the Nicobid dose form of 500 mg niacin per tabletindicate that the side effects have still not been ameliorated, and the main side effect of flushing is still responsible for a patient dropout rate approaching 20%.
35 Therefore, some new method of slow release is required to cope with the specific problem presented by the niacin dose ~orm requirements.
wog3/187~8 2 1 2 ~-~ 3 :J 3 PCI/US93/02804~
-4~
Bearing in mind the problems and deficiencies of the prior art, it is therefore an object of the present invention to provide a composition and method of manuhcture and use which delivers an active pharmaceutical or other ingredients in a dose form to the gastro-intestinal tract of humans and animals over a sustained 5 period.
It is another object of the present invention to provide a composition which delivers niacin, in large dose forms well above 75mg, to the gastro-intestinal tract without the side effects of flushing and itching.
It is a further object of the present invention to provide a sustained release -10 composition and method of manufacture and use which is useful with a wide number of active pharmaceutical and other ingredients.
It is yet another object of the present invention to provide a composition which delivers active pharmaceutical and other ingredients in which the active ingredients may be present in relatively large quantities compared to the remaining cornponents of the composition. --Disclosure of Invention The above and other objects, which will be apparent to those skilled in the art, are prov;ded in the present invention which relates to a simplified method of 20 effecting a clinically validatable slow or sustained release of active pharmaceutical or other ingredients by combining the active ingredient~ with xanthan gum, compacting the combinate and size reducing the compact to form powders or capsules, or by combining the active ingredient with xanthan gum and a suitable lubricant and forming tablets by direct tablet compression techniques.
In one aspect, the invention comprises a compacted sustained release composition for delivering a drug such as niacin as an active ingredient to the gastro-intestinal tract comprising an effective amount of the active ingredient in mixture with xanthan gum, the active ingredient comprising in excess of 40 percent by weight of the total of the active ingredient and the xanthan gum, the mixture30 being in the form of a unit dose in capsule or tablet form. The method corresponding to this aspect comprises producing a compacted sustained release composition for delivering a drug such as niacin as an active ingredient to the gastro-intestinal tract by mixing an effective amount of the active ingredient with xanthan gum, the active ingredient comprising in excess of 40 percent by weight of 35 the total of the active ingredient and the xanthan gum, and forming the mixture in a unit dose in capsule or tablet form.
~'0 93~18758 2 ~ ~. 1 3 5 3 PCr/USg3/02804 In another aspect, the invention comprises a compacted sustained release composition for deli~ering a drug as an active ingredient to the gastro-intest;nal tract comprising an effective amount of the active ingredient in mixture with xanthan gum, the active ingredient being selected from the group consisting of 5 analgesics, antipyretics, anti-inflammatory agents, vitamins, electrolyte replenishers, decongestants, antihistamines, and useful bacteriological organisms for the gastr~
intestinal tract, the mixture being in the form of a unit dose in capsule or tablet form. The method corresponding to this aspect comprises produdng a compacted sustained release composition for delivering a drug as an active ingredient to the 10 gastro-intestinal tract by mixing an effective amount of the active ingredient with xanthan gum, and forming the mixture in a unit dose in capsule or tablet form.
The active ingredient(s) may be agglomerated with a water soluble carbohydrate based agglomerate prior to mixing with the xanthan gum. Preferably,the mixture of active ingredient(s) and xanthan gum is directly compressed into unit 15 dose tablets. Altematively, the mixture of active ingredient(s) and xanthan gum is compacted and reduced in size to fill unit dose capsules.
Modes For CarrYinR Out The Invention Ttie sustained release mechanism of the present invention is based on the 20 concept of phoresis wherein the release rate of niadn or other active pharmaceutical or other ingredient is controlled by producing a tablet which forms - a gel following ingesbon. In order for the niacin or other active ingredient to be released to the gastro intestinal tract in a slow and sustained manner, it is nece,ssary for the ;ngredient to pass uniformly and slowly through the gel. The release of the 25 active component through the gel mass is slow and steady and is controlled by the amount of the gel former used to effect the system.
In accordance with the present invention, xanthan gum has been found to be the most effective gel former used to produce the slow release of niacin or other active ingredient in dose form. Xanthan gum is a high molecular weight 30 natural carbohydrate, or, more specifically, a polysaccharide. Xanthan gum defines the exocellular biopolysaccharide which is produced in a pure culture fermentation process by the microorganism ~Xanthomonas Campestris^. In the fermentation, ~Xanthomonas Campestris~ is cultured in a well aerated medium containing commercial glucose, a suitable nitrogen source, dipotassium hydrogen phosphate, 35 and appropriate trace elements.
The polysaccharide coating formed surrounding the cell wall, xanthan gum, must be stable and hydrophilic in order to protect the organism from dehydration WO 93/18758 ~ 1 2 ~ 3 5 ~ PCI/US93/0280~ r.
during periods o~ adverse conditions. The polymer structure, molecular weight, and gel forming characteristics of the cell wall coating are constant and reproducible under given conditions of fermentation. At the conclusion o~ the fermentation process, xanthan gum is recovered by precipitation in isopropyl 5 alcohol, then dried and milled. The molecular weight of the xanthan gum polymer is probably in the order of 2 million but has been reported to be as high as 13-50 million. These reported differences are most probably due to assodation phenomena between the polymer chains. The xanthan gum is preferably obtained for processing in the present invention in dry, free flowing granular or powder 10 form, with a preferred particle size range of about 20-200 U.S. Mesh (85~74 microns).
In accordance with the present invention, a clinically validatable slow or sustained release of active pharmaceubcal or other ingredients is prepared by combining the active ingredient(s) with xanthan gum, 15 compacting the combinate and size redudng the compact to form powders or capsules, or, in a more preferred embodiment, by combining the active ingredient(s) with xanthan gum and a suitable lubricant and forming tablets by direct tablet compression techniques.
The active pharmaceutical or other ingredients which may be utilized in combination with xanthan gum indude, in addition to niacin (nicotinic acid or 3 pyridine- carboxylic acid), any other pharmaceutical or drug having a beneficialeffect on the body when released to the gastrointestinal tract in a slow or sustained manner. Preferably, the active ingredient or agent is also provided irl dry, free flowing granular or powder form, with a~referred particle size range of about 20-200 U.S. Mesh (850-74 microns). Such ingredients may b`e, for example, analgesic, antipyretic, and/or anti-inflammatory agents such as aspirin, acetamenophen and ibuprofen, vitamins such as pyridoxine (vitamin B 6) hydrochloride and cyanocobalamin (vitamin ~12), calcium ascorbate, eîectrolyte replenishers such as potassium chloride, decongestants such as pseudoephedrine 30 hydrochloride, antihistamines such as chlorpheniramine maleate, or useful bacteriological organisms for the gastro-intestinal tract such as lactobacillus acidophyllus.
The active ingredient or agent may be combined directly with the xanthan gum, as wilî be desaibed below, or may be preliminar;ly combined with a low 35 density, highly porous, generally spherical, water soluble carbohydrate-basedagglomerates of maltodextrin, dextrose, sucrose, *uctose or other agglomerated corn syrup solid, for example. Any of the water soluble carbohydrate-based ~vo 93/187~8 2 1 ? 1~ ~3 r3 3 PCr/US93tO2804 agglomerate may be co-agglomerated with each other prior to or during combination with the active ingredient.
The preferred aggiomerate is maltodextrin, a low conversion starch hydrolyzate having a D.E. (dextrose equivalent) less than 20, an example being 5 VELite 1000 maltodextrin available from Valentine Enterprises, Inc. of Lawrenceville Georgia comprised of Maltrin M-100 maltodextrin available from Grain Processing Corp.
When ehe active ingredient is to be preliminarily combined with the water soluble carbohydrate-based agglomerate, the components are preferably 10 agglomerated in a fluid bed agglomerator by standard spray granulation techniques. The active ingredient is combined with water soluble carbohydrate-based agglomerate and produced as dry, free flowing granules of a desired particle size, for example, about 2~100 U.S. mesh (85~149 microns). The important characteristic is that the active ingredient is contained in or on the carbohydrate-15 based agglomerate and is immediately available, and is stable in the formulationwith the xanthan gum. No coatings such as wax or other compositions are placed over the active ingredient which would interfere with dissolution of the active ingredient. It has been discovered that xanthan gum alone may be employed in the final product to effect slow and sustained release in the20 body.
After the active ingredient is provided in its desired form, either as essentially pure granules or in the agglomerated form described above, it is admixed with the desired amount of xanthan gum, preferably by low shear ~nixing such as that encountered in a planetary, ribbon or plow mixer. The relative 25 amounts of active ingredient and xanthan gum may be varied as desired. It hasbeen unexpectedly discovered that a considerably higher amount of active ingredient, particularly niacin, may be employed relative to the xanthan gum while still retaining the desired effect of slow and sustained release in the gastr~intestinal tract of humans or animals. In particular, the mixture may employ in excess of 40%
30 by weight of active ingred;ent, and even a major amount of active ingredient, in the final dose form, whether it be in compacted and reduced to powder for filling incapsules or directly compressed into tablet form. In the case of niacin as the active ingredient, this is a considerably higher relative amount than can be employed when another gum, such as guar gum, is employed, where limits of 33% by weight 35 of niacin have been reported. In the present invention, the amount of active ingredient may more preferably range from 50-80% by weight of the total mixture, WO 93/18758 PCI /US93/0280~`
2l21~53 -8-and the amount of xanthan gum is preferably not less than 20% by weight, more preferably from 20-50% by weight of the total composition.
After the mixing process, the mixture of active ingredient and xanthan gum is compacted and size reduced, and then made into desired unit dose form such as5 filled capsules. Compaction may be by standard techniques such as slugging where tablets are pressed or by roller compaction. In either case, the compactedtablets or rolls of the mixture are ground to reduce the particle size of the mixture, e.g., to a particle size of about 2~t 00 U.S. mesh (850-149 microns), and then filled into the final capsule dose form. Preferably, to achieve 10 best sustained release characteristics, the mixture may be directly compressed by standard techniques into final tablet dose form. A lubricant such as stearic acid may be added in an amount of 0.1-5% by weight of the total composition to assistin the tableting process.
By following the process of the present invention to produce tablets in the 15 form described, 1000 mg doses of niacin have been able to be formulated in tablets containing xanthan gum in the ranges specified and ingested by humans without a flushing response. Since as little as 75 mg/hr. of niacin has been sl~own to produce flushing, this indicates that the present invention is able to deliver the niacin in slow and/or sustained quanbties over as much as 24 hours or more.
It is theorized that an important function of xanthan gum in the present invention is control of aqueous fluid rheology. It has been found that concentrated aqueous solutions of xanthan gum exhibit extreme pseud~ plasticity. The xanthan gum/active ingredient tablet dose forms a gel sol (a hydrated gel) when exposed to the environment in the stomach. It is believed that when intestinal shear stress is 25 applied to the solvated tablet dose form the viscosity of the xanthan gum gel is reduced and concomitantly spread to allow the drug niac;n to phorese or pass through the gel mass.
Once the xanthan gum/acbve ingredient tablet enters the digestive tract it is subjected to the shear forces of the digestive action and movement which are 30 believed to be sufficient enough to reach the y;eld point of the xanthan gel sol.
The yield point of the xanthan gum sol can be considered to be the quantity of force required to dissociate some of the "super junction zones" of the xanthan gum and the shear thinning that results allows for the spread of the gel sol.
A principal advantage of xanthan over other gums such as guar gum is its 35 greater purity and lot to iot uniformity of composition. Its resistance to bacterial breakdown means also that xanthan feeding adds little short-chain faulty acidsvia bacterial decomposition of the gum in the small or large intestine. It is also wo 93~18758 21 ~ !J 3, ~ PCl`/US93/02804 - g believed to be safe as in reported studies, quantities of 12 g/day of xanthan gum were ingested each day for a period of 12 weeks with no severe adverse digestivesymptoms. In another study, following a 7~ay control period, 5 male volunteers consumed, on each of 23 consecutive days, a weight of xanthan gum equal to 1~
5 times the current accepbble daily intake of 10 mg/kg body weight, as approved by the EEC and by the joint FAO/WHO Expert Committee on Food Additives.
Measurements before and at the end of the test periGd showed that the ingesbon of xanthan, as a prehydrated gel, acted as a bulking agent in terms of its effects on fecal wet and dry weight and intestinal transit times but had no significant effect on 10 plasma biochemistry. Haematological indices, urinalysis parameters, glucose tolerance and insulin tests, serum immunoglobulins" triglycerides, phospholipidsand high density lipoproteins, breath hydrogen and breath methane concentrations. There was, however, a moderate (10%) reduc~on in serum cholesterol and a significant increase in fecal bile acid concentrations. The data 15 indicate that the ingesbon of xanthan caused no adverse dietary nor physiological effects in any of tne test subjects. In particular, all of the enzymatic and other parameters that act as sensitive indicators or adverse toxicological effects remained unchanged.
Positive effects of xanthan ingestion are believed to be its lack of toxicity 20 and also its ability to bind or otherwise increase bile acid content in the feces. It is obvious that any inaease in bile add in the stool will have~a positive effect when dealing with hyperlipidemia. Even though the test quanbties were of a high level, it is apparent that the effect of bile acid elimination and the non formation of free fatty acids is a desirable effect even when the quantities of xanthan are relatively 25 limited. ~
One additional clinica! observation on the use of xanthan gum in obesity can shed some additional light on the use of smaller quantities of xanthan gum to modify semm lipidology. Body weight and cholesterol and triglycerides in blood were estimated in 2 groups of 10 women, 20 to 50 years of age, with body mass 30 index of 3040 before and 3~60 days following ingestion of 2 550 mg capsules of xanthan gum with 250 ml of water 3 times per day or starch placebo capsules with250 ml of water 3 times per day. In each case the capsules were administered before meals. After 30 and 60 days of treatment with xanthan gum body weight decreased by 2.9 and 7.7 kg, cholesterol by 18.8 and 20.5 and triglycerides by 35 12.9 and 15.5 mgl100 ml, respectively. Differences were significant compared with the placebo group. There was also a significant sensation of satiety at 90 min, and at 5 hours after each meal with those subjects on the xanthan gum regimen.
wO 93/187~8 PCI /US93/02~04 ~
2 1 ~ ~ 3 .i ~
Even at this level (3gm xanthan gum/day), significant serum lipid changes were apparent.
Examples The following illustrative examples are given to more particularly illustrate the specific details of the practice of the present invention. Equivalent procedures and quantities will occur to those skillecl in the art and, therefore, the following examples are not meant to define the limits of the present invention, these being 10 defined by the appended claims. All references to percentages in the examples, as throughout the specification, are to weight percentage, unless otherwise identified.
Example 1 Examples of successful niacin/xanthan gum tablet formulations and their method of preparation are as follows: ;
Formulation No. VL5~79 Niacin Base Granulation:
Niacin (Nicotinic Acid) Roche 97.0%
Maltodextrin M-100 3.0%
The niacin was charged into a fluid bed agglomerator and the maltode,xtrin was sprayed over as a 15% aqueous solution to effect agglomeration and 25 compressibility with concomitant good flow characteristics. The ~nal granulation was sized-20 mesh, U.S. sieve size.
Formulation No. VL5~8ûC
Niacin Base Granulation (No. VL5 û79) 61.9%
Xanthan Gum (Keltrol SF) 37.4%
Stearic Acid 0 7%
The components were well mixed and compressed on caplet punches at a 35 weight of 840 mg/tablet at a hardness of 12 kp.
Each 840 mg Tablet yields: Niacin 504.4 mg 87~8 ~ 1 2 ~1 3 S 3 Pcr/uss3/o2xo4 Xanthan Gum 3 14.2 mg Stearic Acid 5.9 mg Maltodextrin 15.5 mg 1 x840 mg Tablet 3x/day yields: Niacin 1500 mg Xanthan Gum 942 mg 2x840 mg Tablets 3x/day yields: Niacin 3000 mg Xanthan Gum1882 mg 3x840 mg Tablets 3x/day yields: Niacin 4500 mg Xanthan Gum~824 mg This formulation was used in tests with subjects to evaluate flushing. No adverse effects have been noted dosing two tablets.
The quantity or percentage composition relative to the xanthan gum has - been raised and lowered from the base formulation (VL5~80C). The least xanthan20 quantity that has, up until now, produced no flushing is noted below.
Formulation No. VL5-11 7E
Niacin BaseGranulation (No. VL5{)79) 76.4% :
Xanthan Gum tKeltrol SF 22.7%
Stearic Acid 0.9%
The materials were mixed and compressed into tablets having a weight of 680 mg at a hardness of 12 kp. ;
Single tablet trials resulted in no adverse flush reaction.
Comparative Example 1 Utilizing the procedure to make the base formulation, No. VL5{)80C, the xanthan gum was replaced with guar gum. After ingestion in test subjects, flushing was found to occur relatively quickly (within 2-3 hours). When half of the xantham gum was replaced with guar gum, flushing occurred after 2 hours. Based upon the 35 trials employed, the effect of slow release of niacin appears to be due to the presence of the xanthan gum and that mixed gum systems of xanthan and guar gum are not as effective.
WO 93/18758 PCI/US93/0280~` :
2 1 2 Lq~ ) ? --1 2 -Results similar to those experienced with guar gum can also be demonstrated with the use of locust bean gum. It appears that guar and locust bean gums are labile to the enzymatic digestive mode. A mixed system of niacin with approximately equal amounts of either guar gum or locust bean gum and 5 xanthan gum results in flushing approximately 2 hours after ingestion of the slow release niacin tablets~ Xanthan gum is believed to be better able to resist ~-enzymatic digestion, liquefication, or in some other manner of destruction of the gel structure than either the guar gum or the locust bean gum.
10 ExamPle 2 Formulation No. VL4~81 Niaàn was agglomerated in a Freund M;ni Flow Coater fluid bed agglomerator as follows:
In Bed:
t 5 Niaàn 400 gm (Lump Free in Fine Powder~ `
In Solution:
Maltrin M-100 (GPC) 12.5 gm Water 112.5 gm Flow Control ~ 55%
Air for atomizabon 10 PSI (Coarse) Spray Rate ~B 3.5 Spray 621 1 Minute Pulse Jet ~ .1& .1 `~
Air Inlet 80C
Terminal Dry 1~l 42 C
Total solution overall will yield 97/O niacin agglomerates Pass agglomerates through 20 mesh The agglomerates *om No~ Vl4 079 were then blended with xanthan gum as follows:
Niacin Base Granulation 61.9%
Xanthan Gum (Keltrol Gm) (coarse granule) 37.4%
Stearic add (fine powder) 0 7%
Blend the materials for 10 minutes then compress on capsule shape punches at 840 mg/tablet at maximum pressure (1~20 KP)~
wos3/l8758 21 ?~353 Pcr/US93/02804 ach tablet yields:
Niacin 504.4 mg Xanthan Gum 314.2 mg Maltrin M-l 00 15.~ mg Stearicacid 5.9 mg Total Tablet Weight 840.0 mg Tablet Weight Spedfication 840.0 mg + 3%
(Average weight 10 tablets) (840 mg-885 mg) 10 2 tablets 3x/day yields:
Niacin 3,000 mg/day Xanthan Gum 1,884 mg/day After taking the aforementioned doses of two niacin tablets, three times per day, the test subjects showed no flushing. Ali of the test subjects showed 15 satisfactory recovery of niacin and nicotinuric acid *om urine.
Thus, the combinate of xanthan gum and r;iacin provides a therapeutic dose form that obviates the flushing reaction associaled with large doses of niacin.
While flush response is usually triggered by approximately 75 mg of niacin, in the combinate of the present invention, we are able to provide dose quantities of 20 niacin of 1000 mg without a flushing response.
Example 3 . .
Agglomerated/granulated niacin base was prepared in a Freund Model 80 fluid ~;
bed agglomerator according to the following formulation:
In Product Container: ~~
Niacin Powder U.S.P. 40 kg Pump Solution:
10 D.E. Maltodextrin Maltrin M-100 (Grain Processing Corp.) 1.23 kg - DistilledWater 11.07 kg Atomizing gun pressure 3.0 atm Atomizing air volume 150 m3/hr Pattern air volume 20 m3/hr The product bowl was secured and fluidization was linitiated with inlet air at 80 C. Alternate spraying a~d shaking of the filters to return un-agglomerated fines WO g3/18758 PCl`/US93/02804~`
to the bowl was continued until all of the pump solution was delivered to the fluidized bed. The product was dried, removed, and sized to -20 mesh and packaged.
A blend for tableting was prepared as follows: -Agglomerated Niacin 61.9%
Xanthan Gum (TIC) 37.4%
Stearic acid (fine powder U.S.P.) 0.7/O
8.0 kg of the prepared blend for tableting was compressed on caplet shaped punches at a w'eight of 840 mg/tablet, with each tablet containing 540 mg of niadn.
A aossover clinical study indicated that the formulation is effective in cholesterol lowering and was essentially flush response free.
Examble 4 Tablets were prepared as follows:
Compression granulated Niadn (Lonza) U.S.P. 60.0% `
Xanthan Gum (Kelco K-7B170) 39.3%
Stearic Acid N.F (fine powder) 0.7% ~ -`
The components were mixed and blended to effect a product suitable for compression.
Tablets were compressed on capsule shaped punches and dies at a weight 25 of 840 m8 to yield tablets containing 504 mg niacin per tablet.
A 6 patient availability indicated satisfactory recovery with no flush;ng following a 2 tablet dose.
Example 5 30 Tablets were prepared as follows:
Niacin fine powder U.S.P. (Roche) 50.0%
Xanthan Gum (fine powder) 49.3%
Stearic Acid (fine powder U.S.P.) 0.7%
6.0 kg of material were blended and further granulated by compaction to yield 20-60 mesh granules. The granules were filled into two piece hard gelatin capsules at a fill weight of 450 mg and contained 225 mg niacin per capsule.
21~ 13~3 ~'O 93/18758 PCl`lUS93/02804 ln a 6 patient evaluation, urinary tracing indicated satisfactory release of theniacin. Two capsule and four capsule dosing equivalent to 500 and 1000 mg niacin per dose indicated no flushing.
Other active ingredients were tested as follows:
Example 6 A tableting base was mixed from the following components:
Acetamenophen (coarse granular) 65.0%
10 Xanthan Gum (granular) 34.3%
Stearic Acid N.F. (fine powder) 0.7%
A 5 kg blend of the tableting base was prepared and pressed into tablets at a weight of 770 mg per tablet equivalent to 500 mg acetamenophen per tablet.
Example 7 15 A tableting base was mixed from the following components:
As~irin (coarse aystals) 61.9%
Xanthan Gum (Keltrol) 37.4% `;
Stearic acid N.F. (fine powder) 0.7%
A 10 kg blend of the tableting base was prepared and pressed into tablets at a weight of 815 mg per tablet equivalent to 500 mg acetylsalicylic acid per tablet.
Example 8 25 A tableting base was mixed from the following components: ~
Ibuprofen powder 60.0%
Xanthan Gum (Keltrol) 39 3%
Stearic acid N.F. (fine powder) 0.7%
A 5 kg of the tableting base was prepared and pressed into tablets at a weight of 667 mg per tablet equivalent to 400 mg ibuprofen per tablet.
Example 9 A tabletin~ base was mixed from the following components:
Potassium chloride USP
(fine crystals) 60.0%
WOg3/18758 2 1 ~ ~ 3 S 3 PCI/US93/0280~
Xanthan Gum (Ketrol) 39.3%
Stearic acid N.F. (fine powder) 0.7%
A 5 kg blend of the tableting base was prepared and pressed into tablets at a weight of 834 mg equivalent to 500 mg of potassium chloride per tablet.
ExamPle 10 A tableting base was mixed from the following components:
Lactobac;llus Achidophylluss 10 ~4 billion organisms/gm) 50.0/O
Xanthan Gum powder (Keltrol) 49.3/O
Stearic ?cid N.F. (fine powder) 0.7%
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 500 mg equivalent to 250 mg of lactobacillus acidophyllus culture per 15 gm (1 billion organisms.) amde 1 1 A tableting base was mixed from the following components:
.
20 Acetamenophen 54.8% 1-Chlorpheniramine Maleate 0.6%
Pseudoephedrine HCI 4.6%
Xanthan Gum 39.3%
Stearic add N.F. (fine powder) 0.7%
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 650 mg. The tablets were equivalent to:
Acetamenophen 356 mg Chlorpheniramine Maleate 30 mg Pseudoephedrine HCI 4 mg Example 1 2 A tableting base was mixed from the foilowing components:
Calcium Ascorbate 65.0%
35 Xanthan Gum 34.3%
Stearic acid N.F. (fine powder) 0.7%
`~'093/187~8 ~ 1 2 ~1 3 5 ~ PCl/US93/02804 A 1 kg blend o~ the tableting base was prepared and pressed into tablets at a weight of 900 mg/tablet. Each tablet was equivalent to 585 mg of ascorbic acid.
Example 1 3 5 A tableting base was mixed from the following components:
Pyridoxine HCI/Maltodextrin Co-agglomerate 65.0%
Xanthan Gum 34.3%
10 Stearic acid N.F. (fine powder) 0.7%
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 650 mg/tablet. Each tablet was equivalent to 50 mg of pyridoxine hydrochloride.
15 Example 14 A tableting base was mixed from the following components:
Cyanocobalamine/Maltodextrin/
Dextrose Co-agglomerate 65~0%
20 Xanthan Gum 34.3%
Stearic acid N.F. (fine powder) 0.7~O
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 650 mg/tablet. Each tablet was equivalent to 75 m~ of cyanocobalamine (vitamin ~12).
The compositions incorporating xanthan gum in the foregoing examples 6-14 exhibit sabsfactory sustained release of the active ingredients therein into the gastro-intestinal tract.
While this invention has been described with reference to specific embodiments, it will be recognized by those skilled in the art that variabons are 30 possible without departing from the spirit and scope of the invention, and that it is intended to cover all changes and modifications of the invention disclosed herein for the purposes of illustration which do not constitute departure from the spirit and scope of the invention.
1 hus, having described the invention, what is claimed is:
As a result of the increased awareness of the importance o~
15 hypercholesterolemia and ik relationship to coronary heat disease during the last several years, there has been an in^reased emphasis on treatment with niacin (nicotinic acid). Guidelines for adults have recently been published by the National Cholffterol Education Program, coordinated by the National Heart, Lung and Blood Institute, which state that a desirable blood cholesterol level is below 5.17 20 mmol/liter. Approximately half of adults screened have been found are encouraged to see a physician for further analysis and instruction. It has been recommended that dinicians use a bile add sequesterant or niacin as first line therapy for treatment of hypercholesterolemic patients. Niacin is also the oldest of the pharmacologic agenk used in the treatment of hyperlipidemia and, since its 25 introduction in 1955, it has been in continuous use either monadically, or in combination with bile add binding resin therapy.
In doses of 3~ g/day, which exceed its requirements as a B Vitamin, niacin ~but not niacinamide) is highly effective in redudng elevated levels of plasma cholesterol and triglycerides. Niacin inhibits adipose tissue lipo!ysis, reduces30 plasma free fatty acid levels and decreases ve~ low density lipoprotein synthesis, thereby decreasing the production of low density lipoproteins from the very low density lipoproteins. Niacin is of demonstrated value in preventing manifestations of arteriosclerotic heart disease, having been shown to decrease recurrent nonfatal myocardial infarction in the coronary drug project by 40% without concurrent 35 increase in mortality from nonarteriosclerotic c~uses as has been obse~ed with clofibrate.
2 1 2 ~ ~ .J 3 ~093/187S8 PCI/US93/02804 Niacin is readily absorbed from the stomach and intestinal tract and has no difficulty passing the tissue barrier. Following per os administration of a tablet or capsule dosage of niacin peak plasma levels are obtained within 15-30 minutes inhumans. Tt e drug is rapidly distributed in the various tissues including kidney and 5 adipose tissue with a slower metabolism of liver and brown fat. Also of note is the observation that niacin has the ability to penetrate the blood brain barrier.
Niacin is rapidly eliminated from plasma and its elimination halflife in humans is 20~5 minutes. Although large doses of 3~ g/day of niacin are required to decrease circulating cholesterol and triglycerides in humans, it does not appear 10 that the high peak serum îevels attained are required, since the lipid lowering effect is maintained after plasma niadn levels are below the limit of sensitivity of the analytical method used. Thus, there is no correlation between systemic levels ofniacin and its pharmacological effect.
The chief drawback to using niacin in the treatment of hyperlipidemia is 15 hdal and truncal flushing, which occurs in nearly all users shortly after ingestion of tablets with as smaii a dosage as 75 mg of niacin per tablet~ It appears that niacin induces flushing by increasing th~ formation and/or release of some prostaglandin, which in turn increases the production of cyclic amp. However, this mechanism does not appear to mediate the effect of niacin on lipolysis. The side effects of 20 truncal flushing, nausea, gastro-intestinal upset, and rectal itching experienced following the ingestion of high potency niacin tablets~ (500 mg/tablet) has contributed to patient dropout of niacin therapy introduced to treat hyperlipidemia.
It has been difficult to produce a slow or sustained release niacin prod~ct by the conventional methods of barrier coating or erosion-type mechanisms. The 25 classic concept of a sustained release dosage regimen is to release 20-35% of the therapeutic agent within the first hour and to sustain the remaining portion of the therapeutic agent over a ~12 hour period. When one considers that the niacin therapeutic dose is 50~1000 mg and that niacin will cause a flushing response inmost subjects with a dosage release of more than 75 mg within a one hour period,30 the problem becomes apparent. Nicobid, marketed by Armour Pharmaceuticals, h~s been the most widely marketed sustained release dose form of niacin in recent y ~rs. Clinical evaluations of the Nicobid dose form of 500 mg niacin per tabletindicate that the side effects have still not been ameliorated, and the main side effect of flushing is still responsible for a patient dropout rate approaching 20%.
35 Therefore, some new method of slow release is required to cope with the specific problem presented by the niacin dose ~orm requirements.
wog3/187~8 2 1 2 ~-~ 3 :J 3 PCI/US93/02804~
-4~
Bearing in mind the problems and deficiencies of the prior art, it is therefore an object of the present invention to provide a composition and method of manuhcture and use which delivers an active pharmaceutical or other ingredients in a dose form to the gastro-intestinal tract of humans and animals over a sustained 5 period.
It is another object of the present invention to provide a composition which delivers niacin, in large dose forms well above 75mg, to the gastro-intestinal tract without the side effects of flushing and itching.
It is a further object of the present invention to provide a sustained release -10 composition and method of manufacture and use which is useful with a wide number of active pharmaceutical and other ingredients.
It is yet another object of the present invention to provide a composition which delivers active pharmaceutical and other ingredients in which the active ingredients may be present in relatively large quantities compared to the remaining cornponents of the composition. --Disclosure of Invention The above and other objects, which will be apparent to those skilled in the art, are prov;ded in the present invention which relates to a simplified method of 20 effecting a clinically validatable slow or sustained release of active pharmaceutical or other ingredients by combining the active ingredient~ with xanthan gum, compacting the combinate and size reducing the compact to form powders or capsules, or by combining the active ingredient with xanthan gum and a suitable lubricant and forming tablets by direct tablet compression techniques.
In one aspect, the invention comprises a compacted sustained release composition for delivering a drug such as niacin as an active ingredient to the gastro-intestinal tract comprising an effective amount of the active ingredient in mixture with xanthan gum, the active ingredient comprising in excess of 40 percent by weight of the total of the active ingredient and the xanthan gum, the mixture30 being in the form of a unit dose in capsule or tablet form. The method corresponding to this aspect comprises producing a compacted sustained release composition for delivering a drug such as niacin as an active ingredient to the gastro-intestinal tract by mixing an effective amount of the active ingredient with xanthan gum, the active ingredient comprising in excess of 40 percent by weight of 35 the total of the active ingredient and the xanthan gum, and forming the mixture in a unit dose in capsule or tablet form.
~'0 93~18758 2 ~ ~. 1 3 5 3 PCr/USg3/02804 In another aspect, the invention comprises a compacted sustained release composition for deli~ering a drug as an active ingredient to the gastro-intest;nal tract comprising an effective amount of the active ingredient in mixture with xanthan gum, the active ingredient being selected from the group consisting of 5 analgesics, antipyretics, anti-inflammatory agents, vitamins, electrolyte replenishers, decongestants, antihistamines, and useful bacteriological organisms for the gastr~
intestinal tract, the mixture being in the form of a unit dose in capsule or tablet form. The method corresponding to this aspect comprises produdng a compacted sustained release composition for delivering a drug as an active ingredient to the 10 gastro-intestinal tract by mixing an effective amount of the active ingredient with xanthan gum, and forming the mixture in a unit dose in capsule or tablet form.
The active ingredient(s) may be agglomerated with a water soluble carbohydrate based agglomerate prior to mixing with the xanthan gum. Preferably,the mixture of active ingredient(s) and xanthan gum is directly compressed into unit 15 dose tablets. Altematively, the mixture of active ingredient(s) and xanthan gum is compacted and reduced in size to fill unit dose capsules.
Modes For CarrYinR Out The Invention Ttie sustained release mechanism of the present invention is based on the 20 concept of phoresis wherein the release rate of niadn or other active pharmaceutical or other ingredient is controlled by producing a tablet which forms - a gel following ingesbon. In order for the niacin or other active ingredient to be released to the gastro intestinal tract in a slow and sustained manner, it is nece,ssary for the ;ngredient to pass uniformly and slowly through the gel. The release of the 25 active component through the gel mass is slow and steady and is controlled by the amount of the gel former used to effect the system.
In accordance with the present invention, xanthan gum has been found to be the most effective gel former used to produce the slow release of niacin or other active ingredient in dose form. Xanthan gum is a high molecular weight 30 natural carbohydrate, or, more specifically, a polysaccharide. Xanthan gum defines the exocellular biopolysaccharide which is produced in a pure culture fermentation process by the microorganism ~Xanthomonas Campestris^. In the fermentation, ~Xanthomonas Campestris~ is cultured in a well aerated medium containing commercial glucose, a suitable nitrogen source, dipotassium hydrogen phosphate, 35 and appropriate trace elements.
The polysaccharide coating formed surrounding the cell wall, xanthan gum, must be stable and hydrophilic in order to protect the organism from dehydration WO 93/18758 ~ 1 2 ~ 3 5 ~ PCI/US93/0280~ r.
during periods o~ adverse conditions. The polymer structure, molecular weight, and gel forming characteristics of the cell wall coating are constant and reproducible under given conditions of fermentation. At the conclusion o~ the fermentation process, xanthan gum is recovered by precipitation in isopropyl 5 alcohol, then dried and milled. The molecular weight of the xanthan gum polymer is probably in the order of 2 million but has been reported to be as high as 13-50 million. These reported differences are most probably due to assodation phenomena between the polymer chains. The xanthan gum is preferably obtained for processing in the present invention in dry, free flowing granular or powder 10 form, with a preferred particle size range of about 20-200 U.S. Mesh (85~74 microns).
In accordance with the present invention, a clinically validatable slow or sustained release of active pharmaceubcal or other ingredients is prepared by combining the active ingredient(s) with xanthan gum, 15 compacting the combinate and size redudng the compact to form powders or capsules, or, in a more preferred embodiment, by combining the active ingredient(s) with xanthan gum and a suitable lubricant and forming tablets by direct tablet compression techniques.
The active pharmaceutical or other ingredients which may be utilized in combination with xanthan gum indude, in addition to niacin (nicotinic acid or 3 pyridine- carboxylic acid), any other pharmaceutical or drug having a beneficialeffect on the body when released to the gastrointestinal tract in a slow or sustained manner. Preferably, the active ingredient or agent is also provided irl dry, free flowing granular or powder form, with a~referred particle size range of about 20-200 U.S. Mesh (850-74 microns). Such ingredients may b`e, for example, analgesic, antipyretic, and/or anti-inflammatory agents such as aspirin, acetamenophen and ibuprofen, vitamins such as pyridoxine (vitamin B 6) hydrochloride and cyanocobalamin (vitamin ~12), calcium ascorbate, eîectrolyte replenishers such as potassium chloride, decongestants such as pseudoephedrine 30 hydrochloride, antihistamines such as chlorpheniramine maleate, or useful bacteriological organisms for the gastro-intestinal tract such as lactobacillus acidophyllus.
The active ingredient or agent may be combined directly with the xanthan gum, as wilî be desaibed below, or may be preliminar;ly combined with a low 35 density, highly porous, generally spherical, water soluble carbohydrate-basedagglomerates of maltodextrin, dextrose, sucrose, *uctose or other agglomerated corn syrup solid, for example. Any of the water soluble carbohydrate-based ~vo 93/187~8 2 1 ? 1~ ~3 r3 3 PCr/US93tO2804 agglomerate may be co-agglomerated with each other prior to or during combination with the active ingredient.
The preferred aggiomerate is maltodextrin, a low conversion starch hydrolyzate having a D.E. (dextrose equivalent) less than 20, an example being 5 VELite 1000 maltodextrin available from Valentine Enterprises, Inc. of Lawrenceville Georgia comprised of Maltrin M-100 maltodextrin available from Grain Processing Corp.
When ehe active ingredient is to be preliminarily combined with the water soluble carbohydrate-based agglomerate, the components are preferably 10 agglomerated in a fluid bed agglomerator by standard spray granulation techniques. The active ingredient is combined with water soluble carbohydrate-based agglomerate and produced as dry, free flowing granules of a desired particle size, for example, about 2~100 U.S. mesh (85~149 microns). The important characteristic is that the active ingredient is contained in or on the carbohydrate-15 based agglomerate and is immediately available, and is stable in the formulationwith the xanthan gum. No coatings such as wax or other compositions are placed over the active ingredient which would interfere with dissolution of the active ingredient. It has been discovered that xanthan gum alone may be employed in the final product to effect slow and sustained release in the20 body.
After the active ingredient is provided in its desired form, either as essentially pure granules or in the agglomerated form described above, it is admixed with the desired amount of xanthan gum, preferably by low shear ~nixing such as that encountered in a planetary, ribbon or plow mixer. The relative 25 amounts of active ingredient and xanthan gum may be varied as desired. It hasbeen unexpectedly discovered that a considerably higher amount of active ingredient, particularly niacin, may be employed relative to the xanthan gum while still retaining the desired effect of slow and sustained release in the gastr~intestinal tract of humans or animals. In particular, the mixture may employ in excess of 40%
30 by weight of active ingred;ent, and even a major amount of active ingredient, in the final dose form, whether it be in compacted and reduced to powder for filling incapsules or directly compressed into tablet form. In the case of niacin as the active ingredient, this is a considerably higher relative amount than can be employed when another gum, such as guar gum, is employed, where limits of 33% by weight 35 of niacin have been reported. In the present invention, the amount of active ingredient may more preferably range from 50-80% by weight of the total mixture, WO 93/18758 PCI /US93/0280~`
2l21~53 -8-and the amount of xanthan gum is preferably not less than 20% by weight, more preferably from 20-50% by weight of the total composition.
After the mixing process, the mixture of active ingredient and xanthan gum is compacted and size reduced, and then made into desired unit dose form such as5 filled capsules. Compaction may be by standard techniques such as slugging where tablets are pressed or by roller compaction. In either case, the compactedtablets or rolls of the mixture are ground to reduce the particle size of the mixture, e.g., to a particle size of about 2~t 00 U.S. mesh (850-149 microns), and then filled into the final capsule dose form. Preferably, to achieve 10 best sustained release characteristics, the mixture may be directly compressed by standard techniques into final tablet dose form. A lubricant such as stearic acid may be added in an amount of 0.1-5% by weight of the total composition to assistin the tableting process.
By following the process of the present invention to produce tablets in the 15 form described, 1000 mg doses of niacin have been able to be formulated in tablets containing xanthan gum in the ranges specified and ingested by humans without a flushing response. Since as little as 75 mg/hr. of niacin has been sl~own to produce flushing, this indicates that the present invention is able to deliver the niacin in slow and/or sustained quanbties over as much as 24 hours or more.
It is theorized that an important function of xanthan gum in the present invention is control of aqueous fluid rheology. It has been found that concentrated aqueous solutions of xanthan gum exhibit extreme pseud~ plasticity. The xanthan gum/active ingredient tablet dose forms a gel sol (a hydrated gel) when exposed to the environment in the stomach. It is believed that when intestinal shear stress is 25 applied to the solvated tablet dose form the viscosity of the xanthan gum gel is reduced and concomitantly spread to allow the drug niac;n to phorese or pass through the gel mass.
Once the xanthan gum/acbve ingredient tablet enters the digestive tract it is subjected to the shear forces of the digestive action and movement which are 30 believed to be sufficient enough to reach the y;eld point of the xanthan gel sol.
The yield point of the xanthan gum sol can be considered to be the quantity of force required to dissociate some of the "super junction zones" of the xanthan gum and the shear thinning that results allows for the spread of the gel sol.
A principal advantage of xanthan over other gums such as guar gum is its 35 greater purity and lot to iot uniformity of composition. Its resistance to bacterial breakdown means also that xanthan feeding adds little short-chain faulty acidsvia bacterial decomposition of the gum in the small or large intestine. It is also wo 93~18758 21 ~ !J 3, ~ PCl`/US93/02804 - g believed to be safe as in reported studies, quantities of 12 g/day of xanthan gum were ingested each day for a period of 12 weeks with no severe adverse digestivesymptoms. In another study, following a 7~ay control period, 5 male volunteers consumed, on each of 23 consecutive days, a weight of xanthan gum equal to 1~
5 times the current accepbble daily intake of 10 mg/kg body weight, as approved by the EEC and by the joint FAO/WHO Expert Committee on Food Additives.
Measurements before and at the end of the test periGd showed that the ingesbon of xanthan, as a prehydrated gel, acted as a bulking agent in terms of its effects on fecal wet and dry weight and intestinal transit times but had no significant effect on 10 plasma biochemistry. Haematological indices, urinalysis parameters, glucose tolerance and insulin tests, serum immunoglobulins" triglycerides, phospholipidsand high density lipoproteins, breath hydrogen and breath methane concentrations. There was, however, a moderate (10%) reduc~on in serum cholesterol and a significant increase in fecal bile acid concentrations. The data 15 indicate that the ingesbon of xanthan caused no adverse dietary nor physiological effects in any of tne test subjects. In particular, all of the enzymatic and other parameters that act as sensitive indicators or adverse toxicological effects remained unchanged.
Positive effects of xanthan ingestion are believed to be its lack of toxicity 20 and also its ability to bind or otherwise increase bile acid content in the feces. It is obvious that any inaease in bile add in the stool will have~a positive effect when dealing with hyperlipidemia. Even though the test quanbties were of a high level, it is apparent that the effect of bile acid elimination and the non formation of free fatty acids is a desirable effect even when the quantities of xanthan are relatively 25 limited. ~
One additional clinica! observation on the use of xanthan gum in obesity can shed some additional light on the use of smaller quantities of xanthan gum to modify semm lipidology. Body weight and cholesterol and triglycerides in blood were estimated in 2 groups of 10 women, 20 to 50 years of age, with body mass 30 index of 3040 before and 3~60 days following ingestion of 2 550 mg capsules of xanthan gum with 250 ml of water 3 times per day or starch placebo capsules with250 ml of water 3 times per day. In each case the capsules were administered before meals. After 30 and 60 days of treatment with xanthan gum body weight decreased by 2.9 and 7.7 kg, cholesterol by 18.8 and 20.5 and triglycerides by 35 12.9 and 15.5 mgl100 ml, respectively. Differences were significant compared with the placebo group. There was also a significant sensation of satiety at 90 min, and at 5 hours after each meal with those subjects on the xanthan gum regimen.
wO 93/187~8 PCI /US93/02~04 ~
2 1 ~ ~ 3 .i ~
Even at this level (3gm xanthan gum/day), significant serum lipid changes were apparent.
Examples The following illustrative examples are given to more particularly illustrate the specific details of the practice of the present invention. Equivalent procedures and quantities will occur to those skillecl in the art and, therefore, the following examples are not meant to define the limits of the present invention, these being 10 defined by the appended claims. All references to percentages in the examples, as throughout the specification, are to weight percentage, unless otherwise identified.
Example 1 Examples of successful niacin/xanthan gum tablet formulations and their method of preparation are as follows: ;
Formulation No. VL5~79 Niacin Base Granulation:
Niacin (Nicotinic Acid) Roche 97.0%
Maltodextrin M-100 3.0%
The niacin was charged into a fluid bed agglomerator and the maltode,xtrin was sprayed over as a 15% aqueous solution to effect agglomeration and 25 compressibility with concomitant good flow characteristics. The ~nal granulation was sized-20 mesh, U.S. sieve size.
Formulation No. VL5~8ûC
Niacin Base Granulation (No. VL5 û79) 61.9%
Xanthan Gum (Keltrol SF) 37.4%
Stearic Acid 0 7%
The components were well mixed and compressed on caplet punches at a 35 weight of 840 mg/tablet at a hardness of 12 kp.
Each 840 mg Tablet yields: Niacin 504.4 mg 87~8 ~ 1 2 ~1 3 S 3 Pcr/uss3/o2xo4 Xanthan Gum 3 14.2 mg Stearic Acid 5.9 mg Maltodextrin 15.5 mg 1 x840 mg Tablet 3x/day yields: Niacin 1500 mg Xanthan Gum 942 mg 2x840 mg Tablets 3x/day yields: Niacin 3000 mg Xanthan Gum1882 mg 3x840 mg Tablets 3x/day yields: Niacin 4500 mg Xanthan Gum~824 mg This formulation was used in tests with subjects to evaluate flushing. No adverse effects have been noted dosing two tablets.
The quantity or percentage composition relative to the xanthan gum has - been raised and lowered from the base formulation (VL5~80C). The least xanthan20 quantity that has, up until now, produced no flushing is noted below.
Formulation No. VL5-11 7E
Niacin BaseGranulation (No. VL5{)79) 76.4% :
Xanthan Gum tKeltrol SF 22.7%
Stearic Acid 0.9%
The materials were mixed and compressed into tablets having a weight of 680 mg at a hardness of 12 kp. ;
Single tablet trials resulted in no adverse flush reaction.
Comparative Example 1 Utilizing the procedure to make the base formulation, No. VL5{)80C, the xanthan gum was replaced with guar gum. After ingestion in test subjects, flushing was found to occur relatively quickly (within 2-3 hours). When half of the xantham gum was replaced with guar gum, flushing occurred after 2 hours. Based upon the 35 trials employed, the effect of slow release of niacin appears to be due to the presence of the xanthan gum and that mixed gum systems of xanthan and guar gum are not as effective.
WO 93/18758 PCI/US93/0280~` :
2 1 2 Lq~ ) ? --1 2 -Results similar to those experienced with guar gum can also be demonstrated with the use of locust bean gum. It appears that guar and locust bean gums are labile to the enzymatic digestive mode. A mixed system of niacin with approximately equal amounts of either guar gum or locust bean gum and 5 xanthan gum results in flushing approximately 2 hours after ingestion of the slow release niacin tablets~ Xanthan gum is believed to be better able to resist ~-enzymatic digestion, liquefication, or in some other manner of destruction of the gel structure than either the guar gum or the locust bean gum.
10 ExamPle 2 Formulation No. VL4~81 Niaàn was agglomerated in a Freund M;ni Flow Coater fluid bed agglomerator as follows:
In Bed:
t 5 Niaàn 400 gm (Lump Free in Fine Powder~ `
In Solution:
Maltrin M-100 (GPC) 12.5 gm Water 112.5 gm Flow Control ~ 55%
Air for atomizabon 10 PSI (Coarse) Spray Rate ~B 3.5 Spray 621 1 Minute Pulse Jet ~ .1& .1 `~
Air Inlet 80C
Terminal Dry 1~l 42 C
Total solution overall will yield 97/O niacin agglomerates Pass agglomerates through 20 mesh The agglomerates *om No~ Vl4 079 were then blended with xanthan gum as follows:
Niacin Base Granulation 61.9%
Xanthan Gum (Keltrol Gm) (coarse granule) 37.4%
Stearic add (fine powder) 0 7%
Blend the materials for 10 minutes then compress on capsule shape punches at 840 mg/tablet at maximum pressure (1~20 KP)~
wos3/l8758 21 ?~353 Pcr/US93/02804 ach tablet yields:
Niacin 504.4 mg Xanthan Gum 314.2 mg Maltrin M-l 00 15.~ mg Stearicacid 5.9 mg Total Tablet Weight 840.0 mg Tablet Weight Spedfication 840.0 mg + 3%
(Average weight 10 tablets) (840 mg-885 mg) 10 2 tablets 3x/day yields:
Niacin 3,000 mg/day Xanthan Gum 1,884 mg/day After taking the aforementioned doses of two niacin tablets, three times per day, the test subjects showed no flushing. Ali of the test subjects showed 15 satisfactory recovery of niacin and nicotinuric acid *om urine.
Thus, the combinate of xanthan gum and r;iacin provides a therapeutic dose form that obviates the flushing reaction associaled with large doses of niacin.
While flush response is usually triggered by approximately 75 mg of niacin, in the combinate of the present invention, we are able to provide dose quantities of 20 niacin of 1000 mg without a flushing response.
Example 3 . .
Agglomerated/granulated niacin base was prepared in a Freund Model 80 fluid ~;
bed agglomerator according to the following formulation:
In Product Container: ~~
Niacin Powder U.S.P. 40 kg Pump Solution:
10 D.E. Maltodextrin Maltrin M-100 (Grain Processing Corp.) 1.23 kg - DistilledWater 11.07 kg Atomizing gun pressure 3.0 atm Atomizing air volume 150 m3/hr Pattern air volume 20 m3/hr The product bowl was secured and fluidization was linitiated with inlet air at 80 C. Alternate spraying a~d shaking of the filters to return un-agglomerated fines WO g3/18758 PCl`/US93/02804~`
to the bowl was continued until all of the pump solution was delivered to the fluidized bed. The product was dried, removed, and sized to -20 mesh and packaged.
A blend for tableting was prepared as follows: -Agglomerated Niacin 61.9%
Xanthan Gum (TIC) 37.4%
Stearic acid (fine powder U.S.P.) 0.7/O
8.0 kg of the prepared blend for tableting was compressed on caplet shaped punches at a w'eight of 840 mg/tablet, with each tablet containing 540 mg of niadn.
A aossover clinical study indicated that the formulation is effective in cholesterol lowering and was essentially flush response free.
Examble 4 Tablets were prepared as follows:
Compression granulated Niadn (Lonza) U.S.P. 60.0% `
Xanthan Gum (Kelco K-7B170) 39.3%
Stearic Acid N.F (fine powder) 0.7% ~ -`
The components were mixed and blended to effect a product suitable for compression.
Tablets were compressed on capsule shaped punches and dies at a weight 25 of 840 m8 to yield tablets containing 504 mg niacin per tablet.
A 6 patient availability indicated satisfactory recovery with no flush;ng following a 2 tablet dose.
Example 5 30 Tablets were prepared as follows:
Niacin fine powder U.S.P. (Roche) 50.0%
Xanthan Gum (fine powder) 49.3%
Stearic Acid (fine powder U.S.P.) 0.7%
6.0 kg of material were blended and further granulated by compaction to yield 20-60 mesh granules. The granules were filled into two piece hard gelatin capsules at a fill weight of 450 mg and contained 225 mg niacin per capsule.
21~ 13~3 ~'O 93/18758 PCl`lUS93/02804 ln a 6 patient evaluation, urinary tracing indicated satisfactory release of theniacin. Two capsule and four capsule dosing equivalent to 500 and 1000 mg niacin per dose indicated no flushing.
Other active ingredients were tested as follows:
Example 6 A tableting base was mixed from the following components:
Acetamenophen (coarse granular) 65.0%
10 Xanthan Gum (granular) 34.3%
Stearic Acid N.F. (fine powder) 0.7%
A 5 kg blend of the tableting base was prepared and pressed into tablets at a weight of 770 mg per tablet equivalent to 500 mg acetamenophen per tablet.
Example 7 15 A tableting base was mixed from the following components:
As~irin (coarse aystals) 61.9%
Xanthan Gum (Keltrol) 37.4% `;
Stearic acid N.F. (fine powder) 0.7%
A 10 kg blend of the tableting base was prepared and pressed into tablets at a weight of 815 mg per tablet equivalent to 500 mg acetylsalicylic acid per tablet.
Example 8 25 A tableting base was mixed from the following components: ~
Ibuprofen powder 60.0%
Xanthan Gum (Keltrol) 39 3%
Stearic acid N.F. (fine powder) 0.7%
A 5 kg of the tableting base was prepared and pressed into tablets at a weight of 667 mg per tablet equivalent to 400 mg ibuprofen per tablet.
Example 9 A tabletin~ base was mixed from the following components:
Potassium chloride USP
(fine crystals) 60.0%
WOg3/18758 2 1 ~ ~ 3 S 3 PCI/US93/0280~
Xanthan Gum (Ketrol) 39.3%
Stearic acid N.F. (fine powder) 0.7%
A 5 kg blend of the tableting base was prepared and pressed into tablets at a weight of 834 mg equivalent to 500 mg of potassium chloride per tablet.
ExamPle 10 A tableting base was mixed from the following components:
Lactobac;llus Achidophylluss 10 ~4 billion organisms/gm) 50.0/O
Xanthan Gum powder (Keltrol) 49.3/O
Stearic ?cid N.F. (fine powder) 0.7%
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 500 mg equivalent to 250 mg of lactobacillus acidophyllus culture per 15 gm (1 billion organisms.) amde 1 1 A tableting base was mixed from the following components:
.
20 Acetamenophen 54.8% 1-Chlorpheniramine Maleate 0.6%
Pseudoephedrine HCI 4.6%
Xanthan Gum 39.3%
Stearic add N.F. (fine powder) 0.7%
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 650 mg. The tablets were equivalent to:
Acetamenophen 356 mg Chlorpheniramine Maleate 30 mg Pseudoephedrine HCI 4 mg Example 1 2 A tableting base was mixed from the foilowing components:
Calcium Ascorbate 65.0%
35 Xanthan Gum 34.3%
Stearic acid N.F. (fine powder) 0.7%
`~'093/187~8 ~ 1 2 ~1 3 5 ~ PCl/US93/02804 A 1 kg blend o~ the tableting base was prepared and pressed into tablets at a weight of 900 mg/tablet. Each tablet was equivalent to 585 mg of ascorbic acid.
Example 1 3 5 A tableting base was mixed from the following components:
Pyridoxine HCI/Maltodextrin Co-agglomerate 65.0%
Xanthan Gum 34.3%
10 Stearic acid N.F. (fine powder) 0.7%
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 650 mg/tablet. Each tablet was equivalent to 50 mg of pyridoxine hydrochloride.
15 Example 14 A tableting base was mixed from the following components:
Cyanocobalamine/Maltodextrin/
Dextrose Co-agglomerate 65~0%
20 Xanthan Gum 34.3%
Stearic acid N.F. (fine powder) 0.7~O
A 1 kg blend of the tableting base was prepared and pressed into tablets at a weight of 650 mg/tablet. Each tablet was equivalent to 75 m~ of cyanocobalamine (vitamin ~12).
The compositions incorporating xanthan gum in the foregoing examples 6-14 exhibit sabsfactory sustained release of the active ingredients therein into the gastro-intestinal tract.
While this invention has been described with reference to specific embodiments, it will be recognized by those skilled in the art that variabons are 30 possible without departing from the spirit and scope of the invention, and that it is intended to cover all changes and modifications of the invention disclosed herein for the purposes of illustration which do not constitute departure from the spirit and scope of the invention.
1 hus, having described the invention, what is claimed is:
Claims (20)
1. A compacted sustained release composition for delivering a drug as an active ingredient to the gastro-intestinal tract comprising an effective amount of said active ingredient in mixture with xanthan gum, said active ingredient comprising in excess of 40 percent by weight of the total of said active ingredient and said xanthan gum, the mixture being in the form of a unit dose in capsule or tablet form.
2. The composition of claim 1 wherein said xanthan gum comprises no more than 60% by weight of the total of said active ingredient and said xanthan gum.
3. The composition of claim 1 wherein said active ingredient is niacin.
4. The composition of claim 1 wherein said active ingredient is selected from the group consisting of analgesics, antipyretics, anti-inflammatory agents, vitamins, electrolyte replenishers, decongestants, antihistamines, and useful bacteriological organisms for the gastro-intestinal tract.
5. The composition of claim 1 wherein said unit dose comprises a major amount by weight of niacin and a minor amount of xanthan gum.
6. The composition of claim 1 further including a water soluble, carbohydrate-based agglomerate.
7. The composition of claim 1 consisting essentially of said active ingredient and said xanthan gum.
8. A method of producing a compacted sustained release composition for delivering a drug as an active ingredient to the gastro-intestinal tract comprising mixing an effective amount of said active ingredient with xanthan gum, said active ingredient comprising in excess of 40 percent by weight of the total of said active ingredient and said xanthan gum, and forming the mixture in a unit dose in capsule or tablet form.
9. The method of claim 8 wherein said xanthan gum comprises no more than 60% by weight of the total of said active ingredient and said xanthan gum.
10. The method of claim 8 wherein said active ingredient is niacin.
11. The method of claim 8 wherein said active ingredient is selected from the group consisting of analgesics, antipyretics, anti-inflammatory agents, vitamins, electrolyte replenishers, decongestants, antihistamines, and useful bacteriological organisms for the gastro-intestinal tract.
12. The method of claim 8 wherein said composition comprises a major amount by weight of niacin and a minor amount of xanthan gum.
13. The method of claim 8 further including combining said active ingredient with a water soluble, carbohydrate-based agglomerate prior to mixing with said xanthan gum.
14. The method of claim 8 wherein said composition consists essentially of said active ingredient and said xanthan gum.
15. A compacted sustained release composition for delivering a drug as an active ingredient to the gastro-intestinal tract comprising an effective, amount of said active ingredient in mixture with xanthan gum, said active ingredient being selected from the group consisting of analgesics, antipyretics, anti-inflammatory agents, vitamins, electrolyte replenishers decongestants, antihistamines, and useful bacteriological organisms for the gastro-intestinal tract, the mixture being in the form of a unit dose in capsuleor tablet form.
16. The composition of claim 15 wherein said active ingredient is selected from the group consisting of aspirin, acetamenophen, ibuprofen, pyridoxine (vitamin B-6) hydrochloride, cyanocobalamin (vitamin B-12), calcium ascorbate, chlorpheniramine maleate, potassium chloride, pseudoephedrine hydrochloride and lactobacillus acidophyllus.
17. The composition of claim 15 wherein said active ingredient comprises in excess of 40 percent and said xanthan gum comprises no more than 60 percent by weight of the total of active ingredient and xanthan gum.
18. A method of producing a compacted sustained release composition for delivering a drug as an active ingredient to the gastro-intestinal tract comprising mixing an effective amount of said active ingredient with xanthan gum, said active ingredient being selected from the group consisting of analgesics, antipyretics, anti-inflammatory agents, vitamins, electrolyte replenishers, decongestants, antihistamines, and useful bacteriological organisms for the gastro-intestinal tract, and forming the mixture in a unit dose in capsule or tablet form.
19. The method of claim 18 wherein said active ingredient is selected from the group consisting of aspirin, acetamenophen, ibuprofen, pyridoxine (vitamin B-6) hydrochloride, cyanocobalamin (vitamin B-12), calcium ascorbate, chlorpheniramine maleate, potassium chloride, pseudoephedrine hydrochloride and lactobacillus acidophyllus.
20. The method of claim 18 wherein said active ingredient comprises in excess of 40 percent and said xanthan gum comprises no more than 60 percent by weight of the total of active ingredient and xanthan gum.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US857,516 | 1977-12-05 | ||
| US07/857,516 US5292534A (en) | 1992-03-25 | 1992-03-25 | Sustained release composition and method utilizing xanthan gum and an active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2124353A1 true CA2124353A1 (en) | 1993-09-30 |
Family
ID=25326166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002124353A Abandoned CA2124353A1 (en) | 1992-03-25 | 1993-03-25 | Sustained release composition and method utilizing xanthan gum and an active ingredient |
Country Status (4)
| Country | Link |
|---|---|
| US (2) | US5292534A (en) |
| EP (1) | EP0632721A4 (en) |
| CA (1) | CA2124353A1 (en) |
| WO (1) | WO1993018758A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6689386B2 (en) | 1996-07-08 | 2004-02-10 | Penwest Pharmaceuticals Co. | Sustained release matrix for high-dose insoluble drugs |
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-
1992
- 1992-03-25 US US07/857,516 patent/US5292534A/en not_active Expired - Lifetime
-
1993
- 1993-03-25 CA CA002124353A patent/CA2124353A1/en not_active Abandoned
- 1993-03-25 WO PCT/US1993/002804 patent/WO1993018758A1/en not_active Application Discontinuation
- 1993-03-25 EP EP93908581A patent/EP0632721A4/en not_active Withdrawn
- 1993-09-16 US US08/122,243 patent/US5427799A/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6689386B2 (en) | 1996-07-08 | 2004-02-10 | Penwest Pharmaceuticals Co. | Sustained release matrix for high-dose insoluble drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0632721A4 (en) | 1996-05-22 |
| WO1993018758A1 (en) | 1993-09-30 |
| US5427799A (en) | 1995-06-27 |
| US5292534A (en) | 1994-03-08 |
| EP0632721A1 (en) | 1995-01-11 |
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