CA1288423C - Pharmaceutical composition containing a carrageenan complex - Google Patents

Abstract

ABSTRACT OF THE INVENTION

A novel complex of carrageenan and a member of the group consisting of doxycycline and propranolol, pharmaceutical preparations containing such a complex, and its use in medicine.

Description

31 ~884~

DESCRIPTION

Techn ica l ~ield The present invention relates to a novel compl~x of S carrageenan and a member o~ the group consisting of : doxycycline and propranolol, and a process for ~he preparation thereof. The invention also relates to novel pharmaceutical compositions containing 3uch a complex of carrageenan and active ingredient, a process for the l0 preparation thereo~ and to the use of the complexes in medicine.

Background Art Doxycycline, which has the structural ~ormula c VH O OH O
is also a therapeutically active ~ubstance~ It i~ ma~nly 15 used in the ~orm of~it~ hydrochloxide. It is:u ed as an antibiotlcally active agent in the treatment of bacterial in~ct~onsO:
.

....

:~.

~1 2~38423 Also, propranolol~ which has the structural formula O-CH2-C~H-CH2-NHCH ICH3) 2 OH

is a known ther~peutically active substance, it is mainly used in the form if its hydrochloride. It is used as a betarec~ptor blocking agent.

The customary mode of administration of doxycycline 1~ by the oral route, mostly in ~he~ form o~ tablets which contain doxycycline in the orm of its chloride together with usual ~nert tablet~ing aids, such as swelling agents. Patien~s ~aking doxycycline hydrochloride tablets are advised to swallow them with water. However, since patients suffering from bladder a~lmen~s at the same time often are advised to reduce their intake of fluid, there is a risk ~hat he tablets aro swallowed with too little water. The tablet may then, when disin~egrating during its paRsage through the 15 esopha~us, ~tlck to the mucosa in the esophagus ~hereby high local concantra~ions o~ doxycycllne hydrochloride are creat~d. Doxycycline hydrochlorlde ha~ irritating effect on ~the mucosa, and such hlgh local concen~ratlons may cause ~evere irritation and ulceration in ~he esophagus.

20 Also, propranolol is mostly adminis~ered orally in the form of tablets containin~ propranolol hydrochloride. Also~ such tablets tend very easily to stick to the mucosa in the esopha~us giving the s~e type of irritation and ulceration as tablets containing doxycycline hydrochloride.

~1 2~384~

Prior Art Certain complexes containing sulated hydrocolloid~, e.g., carrageenan, as complex ~orming agents are d~sclosed in the literature, Reference is made to ~rench patent 5227M, s Journal of Pharmaceutical Sciences, Vol. 50, No. 6, pp.
483-486 (1961); ~ournal of Pharmaceutical Sciences, Vol. 52, No. 2, pp. 192~197 ~1963)s and Journai of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 964-967 (1963~. However, it cannot be inferred rom these cltations that the nov21 complexes of the precent invention would exhibit the properties of binding the active substance sufficiently ~trong in aqueous solution at the pH prevailing in t~e esophagus that only a minor amount while the active substance is released very rapidly in the gastric juice, thus provlding pharmacokinetic properties of the active substance which are quite comparable to the pharmacokinetic properties of the active substance in the presently used salt form.

Detailed Description of the Invention 20 The pre9ent inv~ntion provides a novel complex o~
carrageenan and a member of the group consisting of doxycycline and propranolol. These complexes, which are stable and chemically and physically ~ell-defined entitles, represent an improvemen~ ovex th~ presently used doxycycline 25 hydroc~loride and propranolol hydrochloride as is ~ummariz~d below.

The carxageenan complexes of doxycycllne and propranolol are only sparingly soluble in wa~er. Therefore, the main part o~ the active sub~tanc0 will be compl~x-bound and 30 biologically inactive during the passage of a corresponding tablet through the eso~hagus~ Thi~ graatly reduces the risk : . for irritation and ulceration of the mucosa in tha 0sophagus .

~!-2884Z~

In the gast~o-inte~tlnal Pluids, on the other hand, the active substance is rapidly re'eased from its complex with carrageenan. Therefore, the biological availability of doxycycline and of propranolol will ~e practically 5 equivalent to the biological availability of conventional tablets containing doxycycline hydrochloride and propranolol hydrochloride.

The novel complsx o~ carrageenan and doxycycline and propranolol, ra~pectively, contains a ~uf~icient amount of 10 active substance to make the preparation o~ tablets of suitable size possible. The complex also has suitable properties to admit lts use in the preparation o~ tablets.

The nature of the carrag~enan used to form the complaxes of the invention i 6 not any critical ~actor in the invention.
15 The following spec~ication and example~ w~ll, however, deal wi~h complexes with a speci~ic carrageenan, available undar A ~he trade ~ Aubygum x 2, which now will be identi~ied.

Aubygum x 2 is manufactured by C~CA SA, France, and is a carrageenan-a sulphated polysaccharide. Carrageenan is a 20 hydrocolloid cell consti~uent oE cer~ain red ~eaweed~
belonging to the GigartinaCeae ~amily. The nam~ carrageenan covers a range of sulphated polysaccharides which are compo~ad of galacto~e residues.

Auby~um x 2 ~xist3 mainly aa the sodium salt. It is a 25 linear~poly~acchar1de o~ ~uIphated galactose and 3,6-anhydrogalacto~s~re~sidues and ex~ts ~n two principal fraction~ known as kappa and lambda amounting to about 50-80% and about 20-50~, r~spectively, The molecular weight ~- 18 in the range o~ 100,000 to 1,000,000, .

84~3 IR SPectrum (KBr disc)~
~.
Group Moiety ~and at Wavenumber ~cm 1 -O-H 3700_3000 aliphatic C-H 3000-28Q0 5 water 1640 S-o 1300-1200 C-O (anhydrogalactose) 920 S-O-~ 850 Pr~sence of gala ~ ac~ose: Apart from IR the presence of galactose and 3,6-anhydrogalacfose can be established by thin-layer chromatography.

: White powder, odoxles~ and tasteless.

Viscosi~y: 100-200 mPaS at 25C and not less than S mPaS at 75C using a Brookield viscometer.

: 7-9.5 O~tical rotation: [~] 2Dl ~ 67.8~
(c~0.1718, H2O, Batch No. DjI 159) ~ : 98% thsough 250 ~m 9ieve 20 ~b~s~s Not: mc>re 'chan 1~%, w/w, determined according ~o Karl ~i~cher.

Aubygum x 2 i8 a stable sub~tance.

In clinical use the complexes o~ carrageenan and doxycycline and propranolol, respectively, Will normally be admini~tered 25 orally ln the form of a pharmaceutical preparation which contains the active component optionally in combination wlth ~ S 8 ~2 ~

a pharmaceutically acceptable carrier. The carrier may be in the form o~ a solid, semi~olid, or liquid diLuent, or a capsule. These pharmaceutlcal preparations are a further o~ject of the inven~ion. The complex may also be used 5 without carrier material. Usually the amount of the complex is between 5~ and 99% by weight of the preparation; for example, be~ween 25~ and 80% by weight in prepara~ion~ for oral admini~tration.

In the pr~par~tion of pharmaceutical preparations containing 10 the co~plex in the form of dosage units for oral administration, the complex may be mixed with a solid, pulverulent carrier, such as lac~ose, saccharose, sorbitol, mannitol, a starch such a potato starch, corn starch, or amylopectin, c~llulose derivatives, or gela~in, and may also 15 includ~ a lubricant such as magnesium stearate, calcium stearate, or polyethyleneglycol waxes. The mixture is then pressed into tablets. If c~a~ed tablets are desired, a core prepared as descrlbed above may be coated with a concentrated ~ugar solution which may contain gum arabic, 20 gelatin, talc, titanium dioxide, or alternatively with a lacquer dissolved in volatile organic solvents or mix~ures o~ ~ol~en~s. To this coating various dye~ may be added in order to distlnguish tablets with different actlve compounds or with different amount6 of the active compound present.

25 So~ gelatin capsu}es ma~ be pr~pared which capsules contai~
a mixture of th~ complex and veyetable oil. H~rd~;gelatin capsules may conta~n granules o~ the complex in combination with a solid~ pulverulent carrier as lacto~2, ~accharo~e, sorbitol, mannitol, potato ætarch, corn starch, amylopec~in, 30 cellulose derivatives, or gelatin.

Liquid preparation~ for oral administration may be prepared in the form of syrups or suspensions, e.g., suspensions containing form 0.2~ to 20% by weight of the complex, the 4~3 remainder comprising, for example, sugar and a m xture of ethanol, water, glycerol, and propylene glycol.

The dosage at which the complex is admlnis~ered may vary within a wide range and will depend on variou~ factors such as, for example, the indiv~dual requirements of each patient and the manner of administration. The dosages will be in the same ranges as ordinarily used for doxycycline and propranolol. Thus, in general, oral do3ages of doxycycline will be in the range from 100 to 400 mg/d~y, and oral dosages of propranolol will be from S0 to 500 mg/day.

The ~ollowing examples will illustrate the preparatiQn of ~he complexes of the invention.

10 g doxycycline hydrochloride was dissolved in 100 ml distilled water. 6,4 g carrageenan ~Aubygum x 2) was added during ~tirrlng at room temperature. The slurry was stirred for 30 minutes and, thereafter, ~iltered through a cellulose filter under pressure. The ~ilter cake wa~ disper~ed in 50 ml ~istilled water and the slurry was filtered as before.
20 The humid filter cake was allowed ~o dry overnight at +37C.

The obtalned powder was milled to a particle ~ize below 63 ~m. The powder was analyzed spectrophotometrically after : dis~olution in an aqueous acidic ~odlum chlorida solu~ion snd conta~ned 1.34 mmole doxycycline per gram.

10 g propranolol hydrochloride wa~ dissolved in 100 ml distilled water. 9 g carrageenan ~Aubygum x 2) was added during stirring ~t room temperature. The slurry was stirred for 30 minutes and, thereafter, filtered through a cellulose ~ 2~ 23 filter under pressure. The filter cake was dispersed in 500 ml distilled water and the ~lurry was filtered as before, The humid fil~er cake was granulated through a 10 mesh sieve and allowed to dry overnight at +37C.

The obtained pow~er WaQ milled to a particle 3ize below ~00 ~m. The powder was analyzed spectrophotometrically after dissolution ~n an aqueous sodium chlorl~e solution and contained 1.69 mmole propranolol per gram.

A~ is illustrated in the above examples, the complexes of 10 th~ invention are prepared by reacting a carrageenan or a salt thereof with a solution of doxycycline or propranolol, or a s~lt thereof, followed by isolation o~ the complex formed. Doxycycline and propranolol are suitably used as their hydro~hlorides.

15 The doxycycline carrageenan complex can be prepared by choosing ~he relatlvo amounts o~ carrageenan and doxycycline so that the final complex will contain from 10% to 70% by weight of doxycycline expre~sed a~ doxycycline hydrochloride. Sui~ably, the amount of doxycycline 20 hydrochlorlde in the complex i9 from 50% to 70~ by weight.
The same ranges for tho content of active substance apply also ~or propranolol expressed as propranolol hydrochloride.

Example~o~ usabl~ salts of carrageenan that can be u~ed are ~odium salt and potass~um 5alt~
, 25 The follo~ing ex~mples will illus~rate the compositio~ of pharmaceutical preparatlon~ containing th~ doxycycline-hydrocarragesnate complex and the propranolol-hydrocarra~eenate complex o~ the invention.

~lx~38~,3 Composition of doxycycline-hydrocarrageenate tablets:

I~red nts _ _ _ Con~ent ~ Tablet Doxycycline-hydrocarrageenate 160 mg 5 Magne~ium ~tearate 4 mg Colloidal ~ilicone dioxide 2 mg Polyvinylpolypyrrolidone 20 mg Microcrystalline cellulose (Avicel~)64 mg Average tablet weight 250 mg ~he ~ablets ware produced by a direct compression technique, EX~MPLE 4 Doxycycline-hydrocarrageenate, as prepared in Example 1, was f~lled in capsules to~ether wlth customary excipients, each capsule co~taining 100 mg doxycycline.

~XA~P~ 5 Composi~ion of propranolol hyarocarrageenate tablets:

Ingredients Propranolol hydrocarragaena~e 164 mg Magne~ium stearate ~ : 4 mg 20 Collo~dal silicon2;~dioxi~e ~ 2 mg Polyvlnylpolypyrrolidoné ~ : 20 mg Microc~ystalline cellulose (Avicel~60 mg Average tablet weight 250 mg The tablets were produced by a direct compression technique.

~-2~384~3 Propranolol hydrocarrageenate, a5 prepared in Example 2, was filled in capsules to~ether with customary exclpients, each capsule containing 100 mg propranolol, S BIOLOGICAL TESTS
. __ Tsst of Doxycyclin~ Hydrocarrageenate Tablets Material and Methods Te~t Tablets The tablets tssted were unaoated doxycycline hydro-carrageena~e tablet~, pxepared according to Example 3, corre~ponding to 0.1 g o~ doxycycline hydrochloride, and coated doxycycline hydrochloride 0.1 g tablet6, commercially available Vibramycin~ ~able~s.

ADimals Eight femal~ cats were used or ~he study. The body welght of the animal~ ranged ~rom 2,0 kg to 2.6 kg.

xperimenthl Procedure , ~: Cats ~asted overnight, were anesthetized wlth pentobarbital intravenously at an induction dose of 30 mg/kg~body weight.
The animal~ were placed~:on ~their xight side and kept under : intravenous anesthesia~throughout the exp~riment. Before the admin~st~ation o~ the drug, ~he esophagus was inspected by:use of an endoscope to make sure that the mucous membrane was~normal. Endotracheal intubatlon was als~ per~ormed.

A thread was tied f~rml~ around the tablet to be tested.
The thread was wound around a polyethylene catheter and was ~1 ~884Z3 then, together with the catheter, inserted into a feeding tube with the tablet tied at the end. Thereafter, the.tube was introduced into the esophagus to a specified length.
The tablet was depo~ited by 610w withdrawal of ~he tube with the thread attached to the catheter passing through. The upper end of the thread was sutured to the angle of the lips. The upper end of the catheter was attached to an infusion pu~p. During the ~irst hour o~ doxycycline carrageenat~ tablet exposure, tap water (~-5 ml/h) was instilled into the esophagus close to the table~. The tablet wa~ placed at the b~ginning of the distal thira of the esophagus. The deposition of the VibramyCin~ ta~lets was made in ~he same way, but without inser~ion o~ a.
catheter for inætallation of water, The exposure ~ime was 8 lS hours.

All animals were sacrificed at the end of the exposure period by means of overdosing pentobarbital. A~ter sacriice, the esophagus was dlssected ree and the external aspect was inspected. Thereaftex, the esophagus was opened, 20 in ~ltu. The ~ite of the tablet was ascertained and the disintegration of the tablets, as well as the dissolution/dlsruption of the film coat, were recorded.

The following cri~er$a were used for the assessment of the degxee o~ disintegrat~on o~ the tablets:

~5 + ~he ex~ernal part of ~he~tablet lq moi~t *~ the tablet i`s molst, swollen, and/or 50ft, but withs~ands gen~le pressure +++ the tablet is dissolved, fallen apart, or sof~ned to an sxtent not to withqtand gentle pressure 30 The esophagus then was di~sected free of adnexal ~issue and spread on a cotton clo~h. I~ necessary, the esophageal mucosa was gently rinsed with a few ml of physiological ~ X8~34;~3 saline in order to verify if the tablet material was removable from the mucosal sur~ace or if it stuck to the surface. In many cas~s the macroscopical appearance of the esophagus at the site o the tablet, as well a the tablet S pxoper, w~s recorded by photography. Therea~ter, the esophagus was spread on a blotting paper on which appropriate markings were done as to the macroscopical characteristics o~ the esophagus. Fixation was done in 10%
buffered neu~ral for~alin for 18-48 hours. Paraffin sections wers prepared from a~ least two regions o the esophagu~; accordingly, the esophagus at the sits of the ta~let and a por~ion proximal to the site of the table~.
The paraffin sections, 4-5 microns thick, were stained.

The dissintegra~ion at 8 hour~ o~ the uncoatQd doxycycline hydrocarrageenate tablets corre~ponding to 0.1 g of doxycycline hydrochloxlde was ~(~) or ~ ~i.e., the tablet is moist, swollen, and/or so~t, but with tands gentle pressure) in three of the four cats tested and +++ (i.e., ~he tablet 1R di~ssolved/allen apart or so~tened to an extent no~ to wlthstand gentle pressure) in one cat.

The coated doxycycline hdyrochloride ~Vibra~ycin~) 0.1 g tablets were completely disintegrated at 8 hour~ and ~cored +~+ in all the four ca~s tested.
, The morphological investigation, which comprised macroscopic 25~;and~hi~topathological examination of expoq~d ~sophagi, did not~r~veal any pathological changes in the~esophageal mucosa or wall o~ cats af~er an exposure time of 8 hours with uncoate~ dox~cycline carrageenate tablets corresponding to 0.1 g of doxycycline hydrochloride.

Consistent changes were ~ound in all the cats after 8 hours of exposure with doxycycline hydrochloride (Vibramycin~) 0,1 g tablets. Macroscopically~ the esophagus was ~ ~ ~ 8 ~ 3 yellowish, discolored, and slightly rigid and thin at the site of the tablet. The histopathological ~inding~
consisted in pronounced degenerative changes in the basal portion of the mucosa, slight edema in the propria and focal 5 necrosis of ~uscularis mucosae.

CONCLUSION

No esophageal ixritant effect o~ doxycycline hydrocarrageenate tablets corresponding to O.l g of doxycycline hydrochloride could be revealed using an in vivo 10 cat model in which su~icient disintegratlon of tablets was achieved~ With doxycycline hydrochloride (Vibramyc1 n~) O .1 g tablets, tested under identical conditions, severe morphological changes were observed ~n ~he esophagus.
Hence, khe conclusion is drawn that the new formulation of lS doxycycline, doxycycline carra~eenate, o~fers signi~icantly improved protection agalnst esophago-irritatlon as compared with the commercially available tablet.

Dlssolution Rate o~ s~y_line Hydrocarra~eenate The dissolution rate, according ~o USP XX in chloride 20 buffer, pH 1.2 at ~37~ o~ doxycycline hydrocarrageenate was compared to the dissolution rate of doxycycline hydrochloride using the same procedure. The result was that the dissolution rate of the active substance wa vir~ually undistingui~hable be~ween the two preparation~. This result 25 lndicates that the doxycycline hydrocarrageenate complex of the inven~ion releases the active sub~ance in the gastric juice at the same ra~e as ~he commercially availabl~
preparation~ containing doxycycline hydrochloride.

Claims (34)

1. A process for the preparation of a complex of carrageenan and a member of the group consisting of doxycycline and propranolol by reacting carrageenan, or a salt thereof, with doxycycline, or propranolol, or a salt thereof, in solution.

2. A process according to claim 1 for the preparation of a complex of doxycycline by reacting carrageenan, or a salt thereof, and doxycycline, or a salt thereof, in solution, to the formation of a carrageenan-doxycycline complex.

3. A process according to claim 1 wherein the complex formed is isolated and dried.

4. A process as claimed in claim 1 wherein carrageenan is reacted with doxycycline.

5. A process as claimed in claim 1 wherein carrageenan is reacted with propranolol.

6. A process as claimed in claim 1 wherein the complex is produced in solid form.

7. A process as claimed in claim 1 wherein the complex is produced in dried form.

8. A process as claimed in claim 1 wherein the amount of doxycycline in the product complex is 10% to 70% by weight as doxycycline hydrochloride.

9. A process as claimed in claim 1 wherein the doxycycline or propranolol is present in the complex in an amount of 50% to 70% by weight as the hydrochloride.

10. A process as claimed in claim 1 wherein the propranolol is present in an amount in the complex of 10% to 70% by weight as the hydrochloride.

11. A complex of carrageenan and a member of the group consisting of doxycycline and propranolol when prepared by the process of claim 1 or an obvious chemical equivalent.

12. A complex of carrageenan and doxycycline when prepared by the process of claim 4 or an obvious chemical equivalent.

13. A complex of carrageenan and propranolol when prepared by the process of claim 5 or an obvious chemical equivalent.

14. A complex of carrageenan and propranolol or doxycycline in solid form when prepared by the process of claim 6 or an obvious chemical equivalent.

15. A complex of carrageenan and propranolol or doxycycline in dried form when prepared by the process of claim 7 or an obvious chemical equivalent.

16. A complex of carrageenan and 10% to 70% by weight of doxycycline, calculated as doxycycline hydrochloride, when prepared by the process of claim 8 or an obvious chemical equivalent.

17. A complex of carrageenan and 50% to 70% by weight of a member of the group of doxycycline, calculated as doxycycline hydrochloride and propranolol, calculated as propranolol hydrochloride, when prepared by the process of claim 9 or an obvious chemical equivalent.

18. A complex of carrageenan and 10% to 70% by weight of propranolol, calculated as propranolol hydrochloride, when prepared by the process of claim 10 or an obvious chemical equivalent.

19. A pharmaceutical preparation comprising a complex of carrageenan and a member of the group consisting of doxycycline and propranolol as claimed in claim 11 as active ingredient, and a pharmaceutically acceptable carrier.

20. A pharmaceutical preparation comprising a complex of carrageenan and doxycycline as claimed in claim 12 as active ingredient, and a pharmaceutically acceptable carrier.

21. A pharmaceutical preparation according to claim 19 in a form intended for oral administration.

22. A pharmaceutical preparation according to claim 19 in dosage unit form.

23. A pharmaceutical preparation according to claim 22 in tablet or capsule form.

24. A pharmaceutical preparation according to claim 19 in the form of an aqueous liquid preparation.

25. A pharmaceutical preparation according to claim 24 in the form of an aqueous suspension.

26. The pharmaceutical preparation of claim 21 which is an aqueous liquid suspension containing 0.2% to 20% by weight of said complex.

27. A complex of carrageenan and a member of the group consisting of doxycycline and propranolol.

28. A complex of carrageenan and doxycycline.

29. A complex of carrageenan and propranolol.

30. A complex of carrageenan and propranolol or doxycycline in solid form.

31. A complex of carrageenan and propranolol or doxycycline in dried form.

32. A complex of carrageenan and 10% to 70% by weight of doxycycline, calculated as doxycycline hydrochloride.

33. A complex of carrageenan and 50% to 70% by weight of a member of the group of doxycycline, calculated as doxycycline hydrochloride and propranolol, calculated as propranolol hydrochloride.

34. A complex of carrageenan and 10% to 70% by weight or propranolol, calculated as propranolol hydrochloride.