CA1230556A - Encapsulated antacid dispersions - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Pharmaceutical unit dosage forms comprising dispersions of basic salts in a carrier mixture comprising polyalkylene glycols and a C2-C5 polyol encapsulated in soft gelatin capsules are prepared without deleterious1y affecting the stability of the capsules.

Description

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Il 1230~i;5S ll , ENCAPSULATED ANTACID DISPERSIONS
I , _ 1'; ,, Back~round of the Invention j Soft gelatin en¢apsulat~on of a s~lution or 3¦!di~per~ion of a pharmaceutical agent in a llquid carrler 4 ¦1 offer~ many advantages over other dosage form~ such a~
5~ compre~3ed, coated or uncoated solid tablets or bulk liquid 6I preparatlons. Gelatin ncapQulation of a 801ut~0n or 7, dlqpersion permlt~ accurate dellvery Or a unit dose, an 8l advantage which become~ e~peclally important when relatively 9~ small amounts oP the active ingredient must be del1vered, as lol in the the ca~e of certain hormonea. Such uniformity i~ more 11l difrlcult ~o achieve via a tabletting proce~a wherein ~olidq 12~ must be uniformly mixed and compres~ed, or via incorporation 13 ~ the total dose of acSive 1ngredient into a bulk llquid 14 ;ca~rier whlch mu~t be mea~ured out prlor to each oral 1, ad~ini~tration.
16 l, Soft gelatin encapsulation provides a dosage form 17 l,which is more readily accepted by patlents, since the capsules 18 are easy to swallow and need not be flavored in order to maqk 19 ;the unplea~ant taqte of the active principle. sOrt gelatin cap~ules are al~o more easily transported by patients than 21 ;bulk liquids, Qince only the required number of doses need be 22 I removed from the package.

23 1¦ Soft gelatin encapsulation further provides the 24 1! potential to improve the bioavailability of pharmaoeutical 25 1l agents. Active ingredients are rapidly releaaed in liquid 26 llform a~ soon a~ the gelatin shell ruptureq. Complete 27 1I di~integration and disQolution of the capsule are not 78 i nece~ary for the active ingredients to become available for 29 1! absorption a~ ln the caqe of tabletted oompositions. Al~o, -30 I,relatively ln301uble active ingredlents can be di~persed in a 1~

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I llquid carrier to provide fa~ter ab~orptlon. In the case of 2l an oral liquid preparation, a ~igniflcant amount Or the active 3¦lingredient is lost ln the mouth or esophageal lining, prior to 4 'absorption into the blood.
s !i Currently available antacid preparatlon~ are 6l de~1gned for the sy~ptomatic relief Or heartburn (pyrosis~
7'lsour stomach, indige~tion, ga~ and the hyperacidity as~ociated 8 wlth peptic ulcer, gastritl~, gastric hyperactlvity and hlatal g hernia. These preparations contain one or more basic 101 magnesium, aluminum or calcium ~alt~ which act to neutralize ll stomach acid. For example, MaaloxQ Plus (W.H. Rorer, Inc., 12 ; Ft. Wa~hington, Pa.) is availsble as a liquid which is 13 formulated to deliver 200 mg of magne~ium hydroxide, 225 mg 14 of aluminum hydroxide and 15 mg. of ~imethicone, a gas dispersing agent, per do~e. The tablet ~orm Or this product 16 , is ~lmilar except that it contains 200 mg Or aluminum 1~ ' hydroxide per do~e. Tums~ (Norcllff Thayer, Inc., Tuckahoe, 18 NY) contains about 500 mg of calcium carbonate per tablet.
19 I;Other commerclally available antacid compositions contain varying amounts of magnesium silicate, magne~ium carbonate, 21 bismuth aluminate, magnesium oxide, dihydroxy aluminum sodium 22 carbonate, magaldrate and similar basic salts.
23 ! I The advantages which would be attained by delivering 24 ¦;these salts as disper9ions or solutions via so~t gelatin 25 11 encapsulation have been enumerated hereinabove. However, 26 ~ delivery Or such formulatlons in thi~ manner has not 27 i heretofore been possible due to the chemical destabilization 28 I'i of gelatin, l.e. of type A or B, in the presence of ~trongly 29 j alkaline salts, leading to the leaking or bleeding of the cap~ule contents at elevated pH. Further, the edible oils ll l :tZ30~

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which have traditionally been used as carrlers for pharmaceuticals ln qoft gelatin cap~ules effectively reduce Ij 31,the neutralizing capaclty of the antacid componentq.
4 ¦1 It i~, therefore an ob~ect of the present lnvention s !~ to provlde liquid disper3ion, of basic ~ialts which are 6 !sultable for, and compatable with, soft gelatin encapsulation.
7 It 19 another oblect of the pre~,ent ~n~ention to 8 provide disper~10ns of ba~,ic saltA, e~g., calcium, ~,agnesiu~, 9 and aluminum salts, which are adapted for oral, vaginal, rectal or buccal administration when contalned within ~ioft ll gelatin cap~ule9-12 ~, It i8 another ~ob~ect of the pre ent inYention to 13 provide di,pers~ons of ba~i" salt~ in carriers which do not 14 adversely effect the neutralizing capacity Or the basic salts.
lS Other ob~ects, advantage~, and novel features of the i 16 present invention ~ill be apparent to those of skill ln the 17 ' art from the follo~ing des,cription and appended claims.
18 j! Brief De~,cription Or the Inventlon l9 The ob~ects of the present invention are attained by a pharmaceutical unit do~age form comprising a disper~ion of a 21 I basic salt or salts in a sube~tantially water-free carrier 22 mixture comprising one or more polyalkylene glycols and a C2-23 C5 polyol such as glycerin or propylene glycol. The mixture 24 ,i of alcohols acts to form a ~table dispersion of the particles 25 1 of the ba~ic 9alt which are coated by the carrier mixture and 26 1I renderëd substantially non-reactive with the soft gelatin

2~ ! capsules in which the di9persion is subsequently enclosed.
28 1 Optional amounts of plastic~zers and base-compatible 29 1 pharmaceutical agent~3 may also be incorporated in the -30 lj dispersions of the present invention. ,~

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1 As used herein, the term ~ubstantially water-free"
2ili~ defined to mean that water present in the starting 3ijmaterial3 a8 provided by the manuracturer3 or as ac~uired by 4 1I hygroscopic attraction may be present ln the carrier m{xture, 5 las well a9 minor amount3 of added water wh~ch are insuf~icient 6 lto deleteriou~ly effect the capsule ~all 3tability.
7l Detailed Description of The Invention 8 The compositions Or the present invention permit the g encapsulation, Rtorage and delivery via ort gelatin encap~ulation of ba8ic Yalt~ which would normally be 11l' chemically-incompatible with aoft gelatin if formulated in a 12 dispersior or 301ution ln a pharmaceutically or cosmetically 13 effectlve amount. To overcome thi3 incompatlbility, the basic 14 salt is di9pered in a substantially water-~ree carrier 15 ; compriqing a mixture Or a polyalkylene glycol and a C2-C5 16 ! polyol, e.g. propylene glycol or glycerln. The carrier 17 mlxture i3 ~ormulated ~o as to ~orm a stable disper~ion of the 18 basic ~alt and to coat the salt psrticles 90 a~ to render them 19 substantially non-reactive with soft gelatin. When encapsulated in flexible, soft gelatin capsule~, the disper~ed 21 salt~ do not cause leakage or bleeding Or the disper~ions 22 through the capsule wall~.
23 ¦I The ba~ic salt~ and other compatible active agents ~4 li then remain available rOr oral, reotal, vaginal, buccal or 25 ¦1 topical administration. The basic salts which are disper~ed, 26 11 encapsulated and delivered via the compo~itions o~ the pre~ent 27 1l invention are any of those inorganic or organic metal salts 28 1l which may be incompatible with so~ gelatin, including 29 1I the salt~ of magne~ium, aluminum, ~odium, calcium, bismuth, 30 1! ~inc, zlroonium and titanium.

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~ The di~persions Or the pre~ent invention are 2 particularly ~uited for the dellvery of effectlve amounts Or

3 the commonly-uAed orally-adm~nl~tered antacid ~alt~. The~e 4l~salts include aluminum, magne~ium, sodium and calclum salt~ !
5j such as magnesium hydroxide, ~odium bicarbonate, aluminum 6l~hydroxide~ magneqium oxide, ~agneslum carbonate, calcium 7' carbonate, magnesium silicate, dihydroxy aluminum sodlum ', B carbonate, magaldrate, dihydroxy aluminum aminoacetate, I
9 magnesium phosphate and mixtures thereof. Preferred antacid salts include magne~ium hydrox~de, aluminum hydroxide, calcium ll carbonate and mixtures thereor, due to their high neutralizing 12 power and ab~ence of signi~icant ~ide e~fect~.
13` The amount of the ba~ic salt or ~alts incorporated 14 lnto the antacid di9persions will vary depending on the 15 ~ neutralizing power desired to be dellvered per unit dosage 16 form (e.g., via one capsule contalning up to about 1500 mg of 17 I disperslon- The amount oS encapsulated disperslon will 18 include sur~icient ba~ic ~alt to neutrallze at least about 5 l9 I mEq of hydrochloric acid, preferably ~rom about 5 to about 30 mEq of aqueous hydrochloric acld and most preferably from 21 ' about 5 to about 20 mEq.
' 22 , Other gastrointestlnal agents which are compatible j 23 I with the basic salt may be included in the dispersions of the t 24 ll present inventlon. The9e include the poly~iloxane 25 ¦ flatulence-relieving agent9 8uch as simethiconet which act to 26 I relieve symptoms re9ulting from the retention of exce~sive `
27 gas. Such optional agent9 will typically compri~e about 0-5%
28 l~ by weight Or the total dispersion.
29 1,11 The disperslons of the present in~ention al o permit the so~t gelatin en¢apsulation Or baslc salts such as those ll I. 123~5~ j '. ' l` employed in cosmetic or pharmaceutical ~ormulat~on~ adapted to 2i`deodorize, moisturiZe, protect or heal skin ~la topical 3¦~,appllcation. Such salts lnclude the hydroxides, oxides and 4llcarbonate~ of zinc, ~agnesium, aluminum, ~ircorium or 5 1 i titanium.
6 11 The amount of the ba~c ~alt or salt~ employed a~ a 7 weight percent of the total disper~ion may vary widely 8 depending upon it~ biologlcal activlty and intended u~e, l.e., g ~rom about 5-70S, preferably from about 20-60%.
lOI The liquid carr$er mixture employed to di~perse the ll ba~ic ~alt~ comprlse~ a substantially water-free mlxture of a 12 I maJor proportion of one or ~ore polyalkylene glycols and a 13 ' minor proportion Or a C2-C4 d~ol or triol, preferably 14 ~ PrOPYlene glycol-The polyalkylene glycol component may comprise a 16 ~ polyethylene glyool, a polypropylene glycol or a mixed 17 ' polyethylene~polypropylene glycol having a molecular weight 18 within the range of about lO0-9000. Preferably the l9 polyalkylene glycol co~ponent will ~omprise a mixture of a 20 'ma~or proportion of a liquid polyethylene glycol, i.e., 21 polyethylene glycol-200, 300, 400 or 600 wherein the suffixed 22 1! numbers indicate the approximate molecular weight of the 23 li glycol; and a minor proportion of a waxy polyethylene glycol 24 i having a molecular weight ln the range of about soo-sooo, 25 jl i.e., polyethylene glycol-900, 1000, 1450, 1500, 3350, 3400, 26 ll 4500 o~ 8000. Preferably the ratio of liquid to waxy 27 ~I polyethylene glycol wlll be about 15-40:1, most preferably 28 11, about 20-35:1. Preferably, the polyalkylene glycol will 29 I comprise about 20-80~ by ~eight of the entire dispersion, most 30 l preferably about 30-70S by weight.
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The carrier ~ixture of the present lnvention ~lll 2 ;also comprise a mlnor but effective amount of a C2-C4 pslyol, 3 e.g. a diol or triol such as propylene glycol or glycerin,

4 l ~hlch act~ to ad~u~t the vlsco~ity of the dispersion and to 5l ~tabillze the disperslon. ~ prererred polyol 19 propylene 6I glycol, which uill prererably comprise 0.2-10~ by weight of ? the pre~ent dispersions, mo~t preferably 1.0-3.0S by ~eight.
8 The disper~ione of the pre~ent invention may g optionally comprise m~nor but effective amounts of one or more nonionlc surfactant~ such a~ the C12-C20 fatty acid e~ters of 11 sorbitol and its anhydrides ("Spans~) optionally copolymerized 12 w~th about 15-90 moleY of ethylene oxide (n~weens~). Typical 13 polysorbates which aid in the rormatlon o~ the pre~ent 14 disper~ions and help to stabilize the gelatin cap~ule lnclude poly~orbate 20 (a laurate ester); polysorbate 40 (a palmitate 16 e~ter); polysorbate 60 (a mlxture of ~tearate and palmitate 17 e~ter~); and polysorbate 80 (an oleate ester) wherein the 18 suffixed number~ indicate the approximate mole ratio Or 19 ethylene oxide to ~orbitol. The polysorbates may be present in an amount from about 0-5S by welght of the dispersion. For 21 a general di~cussion Or the properties and composition of the 22 polyethylene glycols and the polysorbates, see Remington's 23 I Pharmaceutical Sciences, A. O~ol, ed., Mack Pub. Co. (16th ed.
24 ,l1980) at pages 1252-1253.

26 1l Therefore, preferred antacid disper~ions formulated 2~ 1 in accord with the present invention will comprise an amount 28 Or basic alumlnum, magnesium, or calcium salt adequate to 29 I;neutrali~e about 5-25 mEq. Or hydrochloric acid per unit do3e;

30 1 about 30-50~ Or a mixture Or a waxy snd a llquid polyethylene 'I

1;'3~ 56 glycol; about 0.2-10~ Or propylene glycol, about 0-5~ o~ a poly~orbate, and about 0-5S o~ a ga~-disperslng ~latulence-llrelieving agent.
4 ¦I The dispersions of the present invention are 5l generally prepared by heating and mixing together the 61, polyalkylene glycol~, rollowed by the room temperature 7 ! addition Or a mixture of the a~tive lngredients, propylene 8 glycol and, optionally~ the polysorhates. The resultant 9l disper3ion is then milled, deaerated, and filled into gelatin 10' capqule~ of a su~ta~le unit do~e size vla a rotary die ll encapsulat10n machine or similar encap~ulating device.
; The lnvention will be further de~crlbed by reference 13 to the following detailed examples.
14 Example I - Hydroxide Dispersion Polyethylene glycol-3350 (182 kg) wa~ disqolved in 16 5586 kg of polyethylene glycol-400 ~ith ~tlrring at 60-C. The 17 solution wa~ then cooled to 30-C. A ~ixture o~ 1400 kg 18 magnesium hydroxide, 1575 kg of aluminum hydroxide (dried l9 alu~inum hydroxide gel --77S) 175 kg Or ~imethicone, 182 kg of 20 ; propylene glycol and 140 kg of polysorbate 80 was stirred into 21 the glycol ~olution over 60 minute The dispersion was Fitz 22 1 ~illed to reduce any remainlng particle aggregates, vacuum-23 1 deaerated and filled into cblong ~oft gelatin (~20) capsules 24 1l at a dose of 1320 mg per capsule. The dispersion batch 25 jl resulted in about 7X106 filled capsule~
26 ¦~ The amount of disper~ion encapsulated (1320 mg) 27, neutralized 10.7 mEq. of hydrochloric acid when titrated 28 1, according to standard methods and gave a preliminary antacid 29 l test reading of pH 7.2 (C.F.R. Title 21, Ch. 1, 331.26 and 30 1 331.253. Under a standard antacid di~integration test, the I _O_ 3~5~
i filled capcule ruptured ln 4.5 min~tes and the ~hell l co~pletely dis~,olved in 9 min. (C.F.R. Title 21, Ch. 1, 3 il ~331.24). These recult~ demonstrate a per unit acid ¦¦neutralizing capacity and antacid availability ~hich are 51 equivalent or superior to Maalox Plus tablet~
li Example II - Carbonate Di~per310n 6, 7 Polyethylene glycol_3350 (140 kg) was di~,olved in a 8 60~C, stirred portlon Or polyethylene glycol-400 (3220 kg~.
g The 30lutlon wa~ cooled to 30-S and 3500 kg o~ calcium li carbonate added with mechan~cal stirring over 1 hr. The l~ , mixture was paR~ed through a Fitz Mill, vacuum deaerated and 12 1000 mg rilled into each of 7 x lo6 ~o~t gelatin capQule~
13~ 14) by mean~ of a rotary die encapsulation machine.
14 ~ One filled capsule neutralized 10.0 mEq of hydrochlorlc acid, gave a preliminary antacid te~t read~ng of 16 ' pH 6.4, ruptured wlthin 3.5 minute~ and the shell dissolved 17 ' within 7.0 ~inutes when te9ted by the procedures of Example I.
18 TheRe results demon~trate a per unit dose acid neutralizing l9 ' capacity and antacid availability which are equivalent or ~uperior to ~ums~ tablets.
21 ,' Preliminary stability testing of filled capsules 22 1 prepared accordin~ to Exs. I or II indicate a pro~ected 23 1 shelf-life of 2-3 years at ambient temperature~ and 24 l' humiditie~. Therefore, examples I and II demonstrate the 25 ¦I preparation of potent encapsulated antacid dispersion~ which 26 ¦1 are qullckly released from the capsule3 in an aqueous acidic 27 lj environment but which do not negatively affect capsule wall 28 ,' stability upon ~torage 29 ~l It iB expected that dispersions formulated according 30 ~I to the present invention w~ll permit the soft-gelatin ! _g_ r 5~ ' liencap~ulation and administration o~ a wide ~ariety of ba~ic 2 "~alt~ useful for pharmaceutical, dletary or cos~etic 3,iappiications, 4 1¦ ~hile certain repre~entative embodiments of the

5!'1nvention have been descrlbed herein for purpo~es o~

6 'illustration, it will be apparent to those ~killed in the art

7 .that modifioation~ therein may be made without departing from

8 the ~p1rit and scope of the invention.

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Claims (24)

WE CLAIM:

1. A pharmaceutical unit dosage form comprising a soft gelatin capsule containing a dispersion of particles of a pharmaceutically-effective amount of a basic salt in a substantially water-free liquid carrier comprising a mixture of polyalkylene glycol and a C2-C5 polyol; said carrier being present in an amount effective to coat the particles of the salt and thereby render them substantially non-reactive with said gelatin capsule.

2. The unit dosage form of claim 1 wherein the basic salt is selected from the group consisting of aluminum, magnesium, sodium and calcium salts.

3. The unit dosage form of claim 2 wherein the basic salt is selected from the group consisting of magnesium phosphate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, dihydroxy aluminum sodium carbonate, magaldrate, dihydroxy aluminum aminoacetate, sodium bicarbonate, calcium carbonate and mixtures thereof.

4. The unit dosage form of claim 1 wherein the polyalkylene glycol comprises a polyethylene glycol and wherein the polyol comprises propylene glycol.

5. The unit dosage form of claim 4 wherein the polyalkylene glycol comprises a mixture of a liquid polyethylene glycol and a waxy polyethylene glycol.

6. The unit dosage form of claim 5 wherein the polyalkylene glycol comprises a mixture of polyethylene glycol 400 and polyethylene glycol 3350 in a weight ratio of about 15-40:1.

7. The unit dosage form of claim 3 wherein the dispersion comprises about 20-60% by weight of the basic salt, bout 20-80% polyethylene glycol and about 0.2-10% propylene glycol.

8. The unit dosage form of claim 7 wherein the dispersion further comprises an effective amount of no more than about 5% by weight of polysorbate.

9. The unit dosage form of claim 8 wherein the basic salt is a mixture of aluminum hydroxide and magnesium hydroxide, the polyethylene glycol is a mixture of polyethylene glycol 400 and polyethylene glycol 3350 and the polysorbate is polysorbate 80.

10. The unit dosage form of claim 9 further comprising an effective flatulence-relieving amount of simethicone.

11. The unit dosage form of claim 7 wherein the basic salt is calcium carbonate and the polyethylene glycol is a mixture of polyethylene glycol 400 and polyethylene glycol 3350.

12. The unit dosage form of claim 6 wherein the basic salt is selected from the group consisting of calcium carbonate, magnesium hydroxide, aluminum hydroxide and mixtures thereof.

13. A product for alleviating the symptoms of ex-cessive gastic acidity comprising an orally administrable soft gelatin capsule containing a dispersion comprising a pharmaceutically-effective amount of an antacid basic salt sufficient to neutralize at least about 5 mEq of hydrochloric acid and a substantially water-free liquid carrier comprising a mixture of polyalkylene glycol and a C2-C5 polyol effective to substantially inhibit degradation of the gelatin capsule by the basic salt.

14. The product of claim 13 wherein the polyol com-prises propylene glycol.

15. The product of claim 14 wherein the basic salt is selected from the group consisting of the salts of magnesium, calcium, sodium, aluminum and mixtures thereof and is present in an amount sufficient to neutralize about 5-25 mEq of hydrochloric acid.

16. The product of claim 14 wherein the polyalkylene glycol is a mixture of a liquid polyethylene glycol having a molecular weight in the range of about 100-700 and a waxy polyethylene glycol having a molecular weight in the range of about 800-9000.

17. The product of claim 16 wherein the weight ratio of liquid polyethylene glycol to waxy polyethylene glycol is about 20-35:1.

18. The product of claim 15 wherein the basic salt is selected from the group consisting of magnesium hydroxide, aluminum hydroxide, calcium carbonate and mixtures thereof.

19. The product of claim 18 wherein the basic salt comprises calcium carbonate and the polyalkylene glycol com-prises about 20-80% by weight of the dispersion of a mixture of polyethylene glycol 400 and polyethylene glycol 3350 in a ratio of about 15-40:1, respectively.

20. The product of claim 18 wherein the basic salt comprises a mixture of aluminum hydroxide and magnesium hydroxide and the polyalkylene glycol comprises about 20-80%
by weight of the dispersion of a mixture of polyethylene glycol 400 and polyethylene glycol 3350 in a weight ratio of about 20-35:1, respectively.

21. The product of claim 19 wherein the propylene glycol comprises about 0.2-10% by weight of the dispersion.

22. The product of claim 20 wherein the propylene glycol comprises about 0.2-10% by weight of the dispersion.

23. The product of claim 20 wherein the dispersion further comprises an effective amount of no more than about 5% by weight of polysorbate.

24. The product of claim 19 wherein the dispersion further comprises an effective amount of no more than about 5% of simethicone.