JP2002528483A - Granular, free-flowing pharmaceutical composition and straw-like dosage form for oral administration thereof - Google Patents

Abstract

  (57) [Summary] The present invention provides a dry, granular, free-flowing, orally-flowable composition comprising particles of a drug or nutrient coated with a suitable taste-masking agent, a hypersalivation inducer, and a pharmaceutically acceptable carrier. A stable pharmaceutical composition having the formula: The present invention also provides a closure comprising a single dosage unit of a pharmaceutical composition of the present invention therein, and provided with opening means for permitting oral administration of the pharmaceutical composition in a dry state. The present invention provides a dosage form for oral administration comprising a water-resistant straw-shaped or non-straw-shaped container.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition for oral administration having a granular, free-flowing and pleasant taste, and a straw-like dosage form for administering the pharmaceutical composition. These forms allow for more convenient and reliable methods of administering a wide variety of drugs and nutrients compared to the difficult cases in using other types of oral dosage forms.

[0002] Orally administered drugs exist in many forms, such as liquid solutions, emulsions, suspensions, capsules, and tablets. Capsule and tablet forms are generally intended for swallowable use. Therefore, it may not be necessary to consider the unpleasant taste of a drug when formulating such a drug, except to block any unpleasant taste while the drug is in the mouth. Many. This can be due to the formation of a thin coating on the tablet that dissolves quickly, using the form of gelatin capsules, or the tablet can be firmly compressed during manufacture, causing the tablet to disintegrate while in the mouth. Can be achieved by not doing so.

A common problem with chewable tablets is that often the unpleasant taste of the active ingredient occurs during chewing. In many cases, the taste of a drug in a tablet is determined by adding a flavoring component to the tablet (to the taste of the flavoring component).
It is possible to superimpose, so that when chewing, the taste of the drug can simply be masked. For example, such treatments are performed in the case of aspirin for infants, where the dosage is small enough to reduce the amount of flavoring ingredients needed to mask the taste of the drug. So that the tablet does not need to be made larger than necessary.

Another approach has been adopted for commercially available infant-size acetaminophen tablets, in which acetaminophen is replaced by ethyl cellulose or cellulose acetate and polyvinyl pyrrolidone. Exists in the form of granules coated with various polymers. While the tablet is in the mouth, most of the acetaminophen is kept shielded by the coating, which can cause partial breakage of the polymer coating due to pressure applied to the tablet during manufacturing. Acetaminophen does not affect taste, despite another disruption of the coating that occurs during chewing. Thereafter, acetaminophen is in a state where it can effectively act from each granular particle when the coating is broken or penetrates the coating. This phenomenon is attributed to the fact that ethylcellulose films are water-permeable, and that a combination film such as cellulose acetate and polyvinyl pyrrolidone dissolves in the gastrointestinal tract, rendering the film water-permeable and dissolving the active ingredient. Due to the inclusion of a soluble component of

[0005] Despite having the effect of masking the unpleasant taste of drugs in tablets and capsules, it is often difficult to swallow such dosage forms of the type described above, such as infants and the elderly. There is still a need for more convenient methods of administering the above drugs to healthy individuals. Even among the broader population, many have reported difficulties in swallowing such tablets and capsules.

[0006] In the case of pediatric medicine, the use of liquids and chewable forms is predominantly performed until infants reach the ages of the order of 10 to 12 years. However, these dosage forms do not address all the needs of infants at this age. For example, in liquid dosage forms, uncertainties in delivery, limited stability (as in the case of antibiotics) after reconstitution (or structural changes in dosage form), and poor There are inconveniences such as a taste. As seen in the case of the elderly, many people require the tablet of the drug to be crushed due to the difficulty of swallowing. In fact, the International Hospital Emissions Research Agency (National Hos
The Pital Discharge Survey shows a 67% incidence of emissions diagnosis of dysphagia in patients over 65 years old (Department of Health, the International Center for Health Statistics) and Human Ser
vices, National Center for Health Statistics (1989)). This incidence is about five times higher than that found in younger patients.

[0007]

Summary of the Invention

The present invention provides a dry, granular, free-flowing, orally-flowable composition comprising particles of a drug or nutrient coated with a suitable taste-masking agent, a hypersalivation inducer, and a pharmaceutically acceptable carrier. A stable pharmaceutical composition having the formula:

[0008] The invention also includes a single dosage unit of a pharmaceutical composition of the invention therein.
The present invention provides a dosage form for oral administration comprising a closed, moisture-resistant straw-shaped container provided with an opening means for allowing oral administration of the pharmaceutical composition in a dry state.

Further, the present invention provides an opening means for containing a single unit dose of the pharmaceutical composition of the present invention therein to enable oral administration of the pharmaceutical composition in a dry state. There is provided a dosage form for oral administration comprising a closed, water-resistant, non-straw-shaped container provided.

[0010]

[Description of preferred embodiments]

The present invention provides a stable and pleasant-tasting pharmaceutical composition having free flow of granules in a dry state for oral administration. The present invention also provides a dosage form employing a straw-shaped container or a non-straw-shaped container for administering the pharmaceutical composition of the present invention. These forms are convenient and reliable methods for administering a wide variety of drugs and nutrients, especially for those who have difficulty using other types of oral dosage forms such as tablets and capsules .

[0011] More specifically, the present invention relates to a method for oral administration comprising a drug or nutrient particle coated with a suitable taste masking agent, a hypersalivation inducer, and a pharmaceutically acceptable carrier. The present invention provides a stable pharmaceutical composition having a granular free flowing property in a dry state.

In one embodiment, the dry composition of the invention has a total moisture content of 10% by weight or less. In a preferred embodiment, the above-described dry composition of the present invention has a total moisture content of 3% by weight or less. As used herein, the term "stable" means physically and chemically stable. This term is well understood in the art and includes, but is not limited to, having a product life of at least about 2 years.

[0013] The drug or nutrition used in the present invention can be any drug or nutrition suitable for oral administration. The types of drugs included in the use in the present invention include:
Including but not limited to analgesics, antacids, antibiotics, decongestants, cough medicines, expectorants, local anesthetics, antihistamines, sympathomimetics, laxatives, and antidiarrheal drugs. Also, the types of nutrients included for use in the present invention include, but are not limited to, minerals such as iron and vitamins such as B ₆ , B ₁₂ , thiamine and folic acid.

A number of analgesics are known in the art, for example, acetaminophen, acetylsalicylic acid, indomethacin, and ibuprofen, naproxen, flurbiprofen, carprofen, thiaprofenic acid, cycloprofen, ketoprofen, Optimally active isomers or racemates such as ketorolac, etodolac, indomethacin, sulindac, fenoprofen, diclofenac, piroxicam, benzidomine, nabumetone and the like, and pharmaceutically acceptable salts thereof, and mixtures thereof. In a preferred embodiment, the analgesic is acetaminophen.

Also, decongestants suitable for use in the present invention include, for example, pseudoephedrine, phenylpropanolamine, phenylephedrine and ephedrine, and pharmaceutically acceptable salts thereof, and mixtures thereof. Cough medicines suitable for use in the present invention include, for example, dextromethorphan, clofedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, benzonate, and pharmaceutically acceptable salts thereof. Salts, and mixtures thereof. Expectorants (also known as mucolytics) useful in the present invention include, for example,
Glyceryl guaiacolate, guaifenesin, terpine hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, and pharmaceutically acceptable salts thereof, and mixtures thereof. Local anesthetics useful in the present invention include, for example, hexylresorcinol, dyclonine, benzocaine, phenol, and pharmaceutically acceptable salts thereof, and mixtures thereof.

Antihistamines useful in the present invention include, for example, chlorpheniramine, brompheniramine, diphenhydramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, azatazine, doxylamine, tripelenamine, cyproheptadine, hydroxyzine, carbinoxamine, phenindamine , Bromodiphenhydramine, pyrilamine, and pharmaceutically acceptable salts thereof,
And mixtures thereof, and acrylastine, AHR-11325, astemizole, azatazine, azelastine, cetirizine, ebastine, ketotifen, rhodoxamide, loratidine, levocabastine, mequitazine, oxatomide,
And non-sedating antihistamines such as cetastatin, tadifylline, temerastin, terfenadine, and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0017] Sympathomimetics suitable for use in the present invention include, for example, pseudoephedrine, phenylpropanolamine, and pharmaceutically acceptable salts thereof (eg, pseudoephedrine hydrochloride), and mixtures thereof. Laxatives that can be used in the present invention include, for example, sennosides A and B. Suitable antidiarrheal agents also include, for example, loperamide and pharmaceutically acceptable salts thereof (eg, loperamide hydrochloride).

As used herein, “pharmaceutically acceptable salts (pharmaceutical salts)
"ly acceptable salts" means salts made with pharmaceutically acceptable non-toxic basic substances, including inorganic basic substances and organic basic substances. Salts derived from inorganic basic substances include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, and manganese salts. Also, as salts derived from pharmaceutically acceptable non-toxic organic basic substances, primary, secondary, tertiary and quaternary amines, substituted amines including naturally substituted amines, cyclic amines Basic ion exchange resins such as amines and triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, generally amino acids, specifically lysine, arginine and histidine, caffeine, procaine, N-ethylpiperidine,
Includes hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purine, piperazine, piperidine, polyamine resin and other salts.

[0019] All of the above drugs, and their acceptable dosage ranges, are described in US Pat.
Nos. 783,465 and 4,619,934. further,
Other cough suppressants, expectorants, antihistamines, sympathomimetics, laxatives, antidiarrheals and analgesics suitable for use in the present invention are Remington's Pharmaceutical Sciences.
tical Science) "(Mack Publishing, Easton, PA, No. 1
8th edition, Chapter 39, Chapter 42, Chapter 43, and Chapter 59 (1990)).

The method of coating drug and nutrient particles used in the present invention with a taste masking agent is well known and commonly utilized in the pharmaceutical industry. Such methods are described, for example, in US Pat. Nos. 5,489,436, 5,260,
Nos. 072, 5,215,755, 5,489,436, and 5,4
Nos. 60,825 and 4,851,224. The taste masking agent is, for example, ethyl cellulose (“EC”), cellulose acetate (“CA”), cellulose acetate butyrate (“CAB”).
), Dimethylaminoethyl methacrylate and neutral methacrylate (
Polymethacrylates such as Eudragit® E-100), hydroxypropyl cellulose (“HPC”), hydroxyethyl cellulose (“HEC”)
, And hydroxypropyl methylcellulose ("HPMC"). Alternatively, drug particles that have already been taste-masked can be purchased. For example, taste-masked acetaminophen is Euron A
merica (Center Drive 845, Bandalia, Ohio, 45377)
Pseudoephedrine (“PE”) which is commercially available from
) And chlorpheniramine maleate ("CPM") particles
ics Inc. (South Hanley Road 2503, St. Louis, MO, 6
3144).

Pharmaceutically acceptable carriers are generally water-degradable hydrocarbons, such hydrocarbons being described in Lieberman et al., “Pharmaceutical Dosage Forms” (
Marcel Dekker, New York, 2nd Edition, Volume 1, pages 205-209, (1990)). Preferred carriers include dextrose, sucrose, lactose, maltose, xylose, maltodextrin, dextrate, mannitol, sorbitol, and xylitol.

[0022] One or more salivary hypersecretion inducers are suitable for the proper digestion of the pharmaceutical composition of the present invention, which has a dry and granular nature. Such pharmaceutical ingredients are routinely used in the art and are usually carboxylic acids. In one embodiment, the salivary hypersecretion inducer is an edible carboxylic acid such as citric acid, malic acid, fumaric acid, benzoic acid, sorbic acid, or adipic acid. Preferably, anhydrous carboxylic acids are used. The use of carboxylic acids in specific formulations is illustrated in the description section for each example below.

In order to improve the taste, mouth sensation, and other physical properties of the drug, the pharmaceutical composition of the present invention comprises further ingredients in addition to the drug, salivary hypersecretion inducer, and carrier described above. It is desirable. Thus, in one example of embodiment, the pharmaceutical composition is further comprised of one or more soothing agents, sweeteners, and flavors. In a preferred embodiment, the composition contains all of these additional components.

Sedatives produce a "cooling" sensation in the mouth due to the endothermic effect of hydration. Such pharmaceutical ingredients are widely used in the art and include, for example, mannitol, sorbitol, and xylitol. Suitable sweeteners also include, for example, aspartame, sucralose, saccharin, cyclamate, acesulfame potassium, mannitol, sorbitol, and xylitol. Suitable flavors include, for example, fruit flavors (eg, lemon flavor) and cream flavors. A more extensive list of sedatives, sweeteners, and flavors is available in the Handbook of Pharmaceutical Excipients, Second Edition.
Edition (American Pharmaceutical Association), Washington, D.C.
C. (1994)).

In one embodiment, the drug composition is comprised of coated acetaminophen particles, citric acid, mannitol, a sweetener, and a lemon flavor. Another more specific embodiment of this composition is described in the Examples section below.

In another embodiment, the coated particles in the pharmaceutical composition of the present invention are composed of a plurality of drugs and / or nutrients. In this case, 2
(I) when the composition is constituted by a single coated particle containing a plurality of drugs and / or nutrients, and (
ii) the composition comprises two or more types of coated particles;
There are cases where each type of particle contains one or more drugs and / or nutrients. In one embodiment, the composition comprises coated acetaminophen particles and chlorpheniramine maleate or pseudoephedrine (
Descote (registered trademark, Particle Dynamics).

The present invention further provides two dosage forms for oral administration. The first form contains a single dosage unit of the pharmaceutical composition of the invention and is provided with closed means for allowing oral administration of the pharmaceutical composition in a dry state. Is constituted by a straw-shaped container. The second form contains a single dosage unit of the pharmaceutical composition of the invention and is provided with closed means for allowing oral administration of the pharmaceutical composition in a dry state. Of non-straw-shaped containers. As used herein, "dry oral a
"dministration" means oral administration which does not require simultaneous ingestion of water or other liquid. In a preferred embodiment of each dosage form of the invention, the coated drug is acetaminophen, the single dosage unit of which is, for example, 50
mg, 80 mg, 160 mg, 300 mg, 325 mg, 500 mg and 10 mg
Contains 00mg.

As used herein, the term “straw-shaped container” refers to any container having a cylindrical shape whose length is greater than its width. The dimensions of the straw-shaped container used in the present invention can be variously changed. In one example of the embodiment,
The dimensions are those of a normal drinking straw, for example having a length of about 200 mm and a width of about 6 mm. This straw-shaped container is made of plastic (for example,
It can be made of any non-toxic, moisture-resistant material, such as polyethylene) or wax-coated paper. Further, the opening means in the straw-shaped container includes an end which opens, for example, by tearing or removing the cap (by twisting or the like). After opening, the contents of the container are simply placed directly into the user's mouth. The straw-shaped container used in the present invention is intended to perform a function similar to the straw-shaped container used in the PIXIE STICK ™ infant granular candy dispenser.

As used herein, the term “non-straw-shaped container” means any container that does not have a cylindrical shape whose length is greater than its width. As with the straw-shaped container, the dimensions of the non-straw-shaped container used in the present invention can be variously changed. For example, the non-straw-shaped container can be a "blister pack" and contains a polymer such as polyvinyl chloride, polyvinylidene chloride ("PVDC") and polychlorotrifluoroethylene ("Aclar (R)"). Is a widely used type of drug container commonly created by Alternatively, the non-straw-shaped container is oval and non-cylindrical, or oval and only partially cylindrical, or cylindrical and has a width greater than its length. It can be. Further, the non-straw container can be a pouch such as a metal foil / metal foil type pouch, a metal foil / paper type pouch, or a paper / paper type pouch. As in the case of the straw-like container, the non-straw-like container can be made of any non-toxic and moisture-resistant material such as plastic or wax-coated paper, the opening means of which is, for example, tear-free. thing,
Or, it includes an end portion opened by removing the cap.

In one embodiment (and in the case of the preferred embodiment of a straw-like dosage form), the dosage form of the invention is packaged with a desiccant in an outer container that is child-safe. Such a child-safe container (the container is 1970
The Toxic Prevention and Packaging Act of 2004 (which meets the requirements of the Federal Law Enforcement Regulations (CFR) Article 16 (1700) and the following paragraphs) and their methods of manufacture are standard elements in the art. Desirably, each outer container has a plurality of individual dosage forms that are administered on an "as needed" basis or periodically over a prescribed length of time. An example based on the former "as needed" criteria is the use of analgesics such as acetaminophen for pain relief. An example based on the latter "regular" criteria is the use of antihistamines such as brompheniramine for reducing seasonal allergic symptoms.

The present invention can be further understood by reference to the following examples, which, if skilled in the art, are merely illustrative of the present invention, It can be readily understood that the present invention is more fully described in the claims appended hereto. In addition, various publications are cited in the present patent application. The disclosures of these publications are incorporated by reference into the present patent application in order to more fully describe the state of the art to which this invention pertains.

Example 1: TYLENOL (acetaminophen) granule-I

[Table 1]

[Table 2]

Example 2: TYLENOL (acetaminophen) granule-II

[Table 3]

[Table 4]

Example 3: TYLENOL (acetaminophen) granule-III

[Table 5]

[Table 6]

Example 4: Granules for sore throat

[Table 7]

[Brief description of the drawings]

FIG. 1 shows a dosage form according to the invention, ie a straw-like dosage form, a pouch-like dosage form,
FIG. 4 is a diagram showing each example of a dosage form in a blister pack.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Bame James S. United States of America, 19341 Pennsylvania Exton, State, Township Line Road 122 F term (reference) 4C076 AA31 BB01 CC01 CC03 CC04 CC15 CC16 CC44 DD38 DD41T DD42T DD43T EE30 EE53 FF52 4C206 AA01 GA02 GA31 KA01 MA03 MA05 MA22 MA61 MA72 NA09 ZA03 ZA08 ZA24 ZA36 ZA63 ZA72 ZB11 ZC13

Claims (15)

[Claims] 1. A dry, granular, free-flowing granule for oral administration comprising a drug or nutrient particle coated with a suitable taste masking agent, a hypersalivation inducer, and a pharmaceutically acceptable carrier. A stable pharmaceutical composition having 2. The method according to claim 1, wherein the drug is an analgesic, a decongestant, a cough remedy, a local anesthetic,
The pharmaceutical composition according to claim 1, which is selected from the group consisting of expectorants, antihistamines, sympathomimetics, laxatives, and antidiarrheal drugs. 3. The pharmaceutical composition according to claim 2, wherein the drug is an analgesic. 4. The pharmaceutical composition according to claim 3, wherein the analgesic is acetaminophen. 5. The pharmaceutical composition according to claim 1, wherein the nutrition is a vitamin. 6. The salivary hypersecretion inducer is citric acid, malic acid, fumaric acid,
The pharmaceutical composition according to claim 1, which is an edible carboxylic acid selected from the group consisting of benzoic acid, sorbic acid, and adipic acid. 7. The pharmaceutical composition according to claim 1, further comprising one or more of a sedative, a sweetener, and a flavor. 8. The pharmaceutical composition according to claim 7, wherein the composition comprises coated acetaminophen particles, citric acid, mannitol, a sweetener, and a lemon flavor. 9. The pharmaceutical composition according to claim 7, wherein the composition comprises coated acetaminophen particles, fumaric acid, mannitol, a sweetener, and a lemon flavor. 10. The pharmaceutical composition according to claim 1, wherein said coated particles contain a plurality of drugs or nutrients. 11. A single dosage unit containing the pharmaceutical composition according to claim 1 and an opening means for allowing oral administration of the pharmaceutical composition in a dry state. A dosage form for oral administration comprising a closed, moisture-resistant straw-shaped container. 12. The dosage form according to claim 11, wherein the drug is acetaminophen. 13. A single dosage unit containing the pharmaceutical composition according to claim 1 and having opening means for allowing oral administration of the pharmaceutical composition in a dry state. A dosage form for oral administration comprising a closed, water-resistant, non-straw-shaped container. 14. The dosage form according to claim 13, wherein said drug is acetaminophen. 15. The dosage form according to claim 11, wherein the dosage form is packaged together with a desiccant in an outer container safe for children.