United States Patent: 6,027,746
Inventors: Lech; Stanley (Rockaway, NJ)Assignee: Warner-Lambert Company (Morris Plains, NJ)
Appl. No.: 064324Filed: April 22, 1998
The present invention relates to novel liquid oral suspensions incorporated within a soft gelatin capsule comprised of a bitter or bad-tasting pharmaceutical active (such as antihistamines, decongestants and the like) which is dispersed within an adsorbate comprised of magnesium trisilicate, silicon dioxide or mixture thereof. The adsorbate is dispersed within an aqueous or non-aqueous carrier base and combined with other flavors, sweeteners, emulsifiers and the like. The adsorbate not only taste-masks the active but also insures that is evenly dispersed through the liquid suspension so that a uniform dosage rate is readily achievable. The encapsulation of the adsorbate within a gelatin capsule makes administration easier for children andmore convenient. The capsule also affords the adsorbate suspension greater shelf life.
DETAILED DESCRIPTION OF THE INVENTION
Chewable tablets and capsules are highly valuable forms of
oral pharmaceutical delivery systems in both the prescription and over the
counter markets due to the convenience of their administration; i.e., no
water is necessary. However, the bitter or unpalatable tastes of most
drugs has severely limited their acceptance in these markets. The present
invention seeks to overcome these limitations by affording a chewable
gelatin capsule in which the bitter taste of the drug has been masked
through the use of a drug adsorbate disposed therein together with other
pleasant tasting syrup carriers, flavors, sweeteners and the like.
The adsorbate suspension technology of the present invention that is
incorporated within the gelatin capsule is comprised of a pharmaceutical
active adsorbed onto a magnesium trisilicate microgranule or agglomerate.
The drug/adsorbate composition is dispersed in an aqueous or non-aqueous
carrier solvent which is then injected into a chewable gelatin capsule so
the drug can be ingested and readily adsorbed into the patient's stomach
for quick relief. With magnesium trisilicate adsorbate technology, the
present invention can provide chewable encapsulated liquid suspensions
that would otherwise be bitter tasting, with superior taste to other drug
delivery systems known in the art. Moreover, despite the presence of the
solid adsorbate, there is no gritty texture due to the preparation of the
adsorbate in a very small particle size. The gelatin capsules known in the
art generally must be swallowed whole which again is a problem for
children, the elderly and others who have difficulty in swallowing.
Magnesium trisilicate (Mg(O.sub.3 S).sub.3) is a fine, white odorless and
tasteless powder that is a well known adsorbent, antioxidant and antacid.
The compound is an excellent adsorbate carrier for pharmaceutical agents
as it can form flake-like lattice structures with many interstitial spaces
that provides a large surface area for maximum drug loading. When
solubilized in an aqueous-solution containing the drug of interest, the
flakes can then be precipitated as masses with the drug adsorbed within
the interstitial crevices between the individual flakes. The drug
adsorbate is then mixed within the carrier fill which is encapsulated by
the soft gelatin capsule.
Silicon dioxide, (SiO).sub.2) or silica is a second substance useful as
the adsorbate for the active agent in the practice of the present
invention. A colorless crystalline powder, it also may be precipitated
from solution as clumped flakes with interstitial spaces in which the
active pharmaceutical is trapped and adsorbed. Preferably, the adsorbate
used in the practice of the present invention is comprised of a mixture of
both magnesium trisilicate and silicon dioxide in a 1:1 ratio.
The pharmaceutical agent useful in the delivery system of the present
invention could conceivably be any active drug capable of delivery by oral
administration. For example, suitable pharmaceuticals might include anti-tussives,
antacids, analgesics, antihistamines, anti-arrythimics, decongestants,
anti-inflammatory agents, central nervous system drugs, diuretics,
antidiarrheal compounds, steroids, antibiotics, chemotherapeutic agents,
neoplastic agents, antiparasitic agents and the like. The only criteria as
to whether the drug would be useful in the chewable delivery system is
whether it can provide its therapeutic effect after ingestion and
absorbation and its compatibility with the filler material and chewable
gelatin shell. Other criteria to consider is the drug's dissolution rate
and shelf life stability.
Conceivably the, the specific therapeutic agent useful in the practice of
the present invention can be any one of the many pharmaceutical agents
that may be delivered orally, ingested, and then absorbed through the
digestive tract and into the bloodstream. Preferably however, the drug
active is both water soluble and one of the many unpleasant tasting drugs
currently available on the Rx and over the counter market. Pharmaceutical
actives of this type include antitussive compounds such as
dextromethorphan, detromethorphan hydrobromide, noscapine, carbetapentane
citrate, chlorphedianol hydrochloride and the like; sedating
antihistamines include chlorphenramine, phenidamine, doxylamine,
phenylOxamine, diphenhydramine, promethazine and triprolidine, hydroxyzine,
meclinzine, cyproheptadine, azatadine their salts and mixtures thereof.
Suitable non-sedating antihistamines include fexofenadine, terfenadine,
astemizole, loratadine and cetirizine, while suitable decongestants
include phenylephrine, phenylpropanolamine, pseudoephedrine, ephedrine,
theirs salts and mixtures thereof.
Nonsteroidal anti-inflammatory agents (NSAIDS) may also be incorporated in
the absorbate compositions of the present invention. Suitable NSAIDS
include ibuprofen, ketoprofen, acetylsalicylic acid, ketoprofen, aproxen,
naprosyn, meclomen, indomethicin and mixtures thereof. Suitable analgesics
include acetaminophine. H.sup.2 -antagonists useful in the composition of
the present invention include famotidine, ranitidine, cimetidine and
mixtures thereof.
Useful antibiotics, antibacterials and bactericidals include erythromycin,
cephalosporin, tetracyclines, penicillin, amoxycillin, clathromycin and
mixtures thereof. Useful anti-convulsants include phenyltoin and
thosuximide.
The wide variety of pharmaceuticals useful herein include their acid
addition salts. Both organic and inorganic salts may be used and exemplary
acid salts include the hydrochloride, hydrobromide, orthophosphate,
benzoate, maleate, tartrate, succinate, citrate, salicylate sulfate,
acetate and mixtures thereof.
The pharmaceutical or therapeutic agent is preferably first dissolved in
water or some other organic solvent for those drugs which are not water
soluble. Depending on the dosage desired, and the type of drug involved,
the drug is added in an amount of from 0.5% to about 25% w/w of the
absorbate. Once complete dissolution of the active has occurred, the
solution is added to the absorbate in amounts of from about 0.1 to about
3.0 mls. per gram of absorbate. The preferred absorbate for the use in the
practice of the present invention is magnesium trisilicate (2MgO.sub.3
SiO.sub.2 H.sub.2 O) or silicon dioxide (SiO.sub.2) and most preferably a
combination of the two. The magnesium trisilicate and silicon dioxide are
very fine, white, odorless powders with flake-like structures with
multiple interstitial spaces.
Once the pharmaceutical solution is prepared, it is added to the magnesium
trisilicate/silicon dioxide powder and a slurry is prepared as the
absorbate and drug are combined. The absorbate/drug carrier agent is then
dispersed into a non-aqueous or aqueous base using a moderate to high
sheer mixer.
Suitable non-aqueous bases may be selected from the group comprising
vegetable oils and fats, animal fat, mineral oils, paraffin and wax,
natural fatty acids any edible oil, glycerin, sugar and mixtures thereof.
Suitable aqueous-based solvents include water with a second excipient
comprised of sorbitol, glycerine, corn syrup, sugar, alcohols and mixtures
thereof.
Again, the amount of pharmaceutical active incorporated into the
magnesium/silicate will vary depending on the target dosage and the type
of drug to be taste masked. Generally, the active will be mixed in amounts
of from 0.2 grams to about 0.3 grams per gram of absorbate. The amount of
active absorbate per volume of liquid carrier will also vary but generally
may be from about 1.0% to about 15% active/adsorbate based on the total
weight percent (wt %) of the liquid formulation.
The filler composition that carries the adsorbate within the soft chewable
shell is comprised of flavors, sweeteners, colorants, solvents,
preservatives, polyethylene glycol, corn syrup, emulsifiers,
gums/thickeners, oils and fat fillers and other insoluble or soluble
excipients. The specific components of each genus can be readily
ascertained by those skilled in the art. Flavor and component
compatibility are perhaps the major criteria in the excipient selection.
In formulating the final suspension product, additional excipients such as
flavoring agents, preservatives, gums/thickeners, sweeteners, coloring
agents, emulsifiers, fillers, oils and fats and the like may be added to
the encapsulated oral suspension to further improve the taste and
palatability thereof during chewing. These can be added in varying amounts
as is known in the art and as desired according to the formulation.
Generally, a standard liquid will be comprised of the following components
in their respective amounts, based on the total weight percent of the
liquid suspension.
______________________________________
Compositions Percentage
______________________________________
Drug adsorbate 1.00-15.00%
Sorbitol 5.00-90.00%
Water 10.00-80.00%
Preservatives 0.01-1.00%
Glycerin 5.00-30.00%
Gums/thickeners 0.500-5.00%
Flavors 0.500-4.00%
Buffers 0.500-5.00%
______________________________________
In order to prepare the adsorbate suspensions incorporated in the gelatin capsule of the present invention, generally a wet granulation methodology is employed as is known in the art. If magnesium trisilicate is used as the sole adsorbate carrier, it is important to maintain the pH of the process and that of the product as well at a pH of about 8.5 in order to maintain the stability of the trisilicate. If silicon dioxide is employed as the sole adsorbate, pH is of no consequence, but again, this is not preferred. Most preferably a combination of the two is employed wherein pH will not be a major factor of concern. Nevertheless, maintaining a pH as close to 8.5 as possible will produce a better final product.
The soft chewable capsules of the present invention are generally comprised of plasticized gelatin or a pharmaceutically acceptable polymer. The capsule itself is a one-piece, sealed construction enclosing the components therein. Soft capsules are generally used for encapsulating a fluid carrier, a semi-fluid carrier or both. The difficulty in using gelatin as the drug matrix shell is the inherent and marked affinity of the gelatin capsules for water. Usually, special considerations must be taken to keep the water content of the filler material below a critical minimum, otherwise the carrier medium may be adsorbed into the gelatin shell resulting in its degradation and breakdown.
The gelatin capsules are generally comprised of natural or synthetic polymers as is known in the art. Natural gelatin, pectin, casein, collagen, protein, modified starches, polyvinyl pyrolidone and the like are all capsule components well-known in the art. Gelatin is the composition of choice and may be combined with stabilizers, plasticizers and coloring agents as is known in the art. Specific capsules useful in the practice of the present invention and methods for their preparation are described in U.S. Pat. Nos. 4,325,761 and 4,281,763 to Pace, 4,532,126 to Ebert et al. and 4,780,316 to Brox et al., all of which are incorporated by reference.
The filler materials described above may therefore be dispersed in a water immiscible solvent or oil as a carrier medium within the shell. This will also serve as the carrier medium within which the drug adsorbate is dispersed prior to encapsulation.
The gelatin capsule itself is generally ovoid in shape and can be sized according to the potency of the drug and dosage. Other shapes can be utilized according to individual preference although ovoid is generally preferred. Gelatin encapsulation methodologies are well-known in the art, and large scale commercial means are described in U.S. Pat. No. 4,922,682 to Tart et al., U.S. Pat. No. 4,997,359 to Lebrun and Re 33,251 to Wittmer et al., all which are also incorporated by reference.
Claim 1 of 15 Claims
1. An oral pharmaceutical delivery system comprising a
liquid pharmaceutical suspension for the oral delivery of an unpleasant
tasting active agent consisting of a particulate adsorbate with the active
medicament contained therein dispersed in an aqueous or non-aqueous
carrier solvent encapsulated within a soft, chewable gelatin capsule.
____________________________________________
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