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Sommaire du brevet 1288423 

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Disponibilité de l'Abrégé et des Revendications

L'apparition de différences dans le texte et l'image des Revendications et de l'Abrégé dépend du moment auquel le document est publié. Les textes des Revendications et de l'Abrégé sont affichés :

  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Brevet: (11) CA 1288423
(21) Numéro de la demande: 464529
(54) Titre français: COMPOSE PHARMACEUTIQUE CONTENANT UN COMPLEXE DE CARRAGENINE
(54) Titre anglais: PHARMACEUTICAL COMPOSITION CONTAINING A CARRAGEENAN COMPLEX
Statut: Périmé
Données bibliographiques
(52) Classification canadienne des brevets (CCB):
  • 167/184
  • 167/199
  • 260/223
  • 260/208.1
(51) Classification internationale des brevets (CIB):
  • C08B 37/12 (2006.01)
  • A61K 31/715 (2006.01)
(72) Inventeurs :
  • BERGWITZ-LARSEN, CARL-AAGE (Suède)
  • OSTERLUND, ROLF GUSTAV LENNART (Suède)
(73) Titulaires :
  • KABI PHARMACIA AKTIEBOLAG (Suède)
(71) Demandeurs :
  • BERGWITZ-LARSEN, CARL-AAGE (Suède)
  • OSTERLUND, ROLF GUSTAV LENNART (Suède)
(74) Agent: BORDEN LADNER GERVAIS LLP
(74) Co-agent:
(45) Délivré: 1991-09-03
(22) Date de dépôt: 1984-10-02
Licence disponible: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Non

(30) Données de priorité de la demande: S.O.

Abrégés

Abrégé anglais






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.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.



THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS:

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-


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.


- 15 -


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.




PAT6740-1




-16 -

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.


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
CH3 OH 1 CH3


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 1100-1000
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.

EXAMPLE 1

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.

EXAMPLE 2

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


EXAMPLE 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


EX 6

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.

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États administratifs

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , États administratifs , Taxes périodiques et Historique des paiements devraient être consultées.

États administratifs

Titre Date
Date de délivrance prévu 1991-09-03
(22) Dépôt 1984-10-02
(45) Délivré 1991-09-03
Expiré 2008-09-03

Historique d'abandonnement

Il n'y a pas d'historique d'abandonnement

Historique des paiements

Type de taxes Anniversaire Échéance Montant payé Date payée
Le dépôt d'une demande de brevet 0,00 $ 1984-10-02
Enregistrement de documents 0,00 $ 1985-03-11
Enregistrement de documents 0,00 $ 1993-06-11
Taxe de maintien en état - brevet - ancienne loi 2 1993-09-03 100,00 $ 1993-07-12
Taxe de maintien en état - brevet - ancienne loi 3 1994-09-05 100,00 $ 1994-08-19
Taxe de maintien en état - brevet - ancienne loi 4 1995-09-04 100,00 $ 1995-08-17
Taxe de maintien en état - brevet - ancienne loi 5 1996-09-03 150,00 $ 1996-08-19
Taxe de maintien en état - brevet - ancienne loi 6 1997-09-03 150,00 $ 1997-08-20
Taxe de maintien en état - brevet - ancienne loi 7 1998-09-03 150,00 $ 1998-08-19
Taxe de maintien en état - brevet - ancienne loi 8 1999-09-03 150,00 $ 1999-08-18
Taxe de maintien en état - brevet - ancienne loi 9 2000-09-04 150,00 $ 2000-08-16
Taxe de maintien en état - brevet - ancienne loi 10 2001-09-03 200,00 $ 2001-08-07
Taxe de maintien en état - brevet - ancienne loi 11 2002-09-03 200,00 $ 2002-08-08
Taxe de maintien en état - brevet - ancienne loi 12 2003-09-03 200,00 $ 2003-08-05
Taxe de maintien en état - brevet - ancienne loi 13 2004-09-03 250,00 $ 2004-08-09
Taxe de maintien en état - brevet - ancienne loi 14 2005-09-05 250,00 $ 2005-08-08
Taxe de maintien en état - brevet - ancienne loi 15 2006-09-05 450,00 $ 2006-08-08
Taxe de maintien en état - brevet - ancienne loi 16 2007-09-04 450,00 $ 2007-08-06
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
KABI PHARMACIA AKTIEBOLAG
Titulaires antérieures au dossier
BERGWITZ-LARSEN, CARL-AAGE
KABIVITRUM AB
OSTERLUND, ROLF GUSTAV LENNART
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
Documents

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Liste des documents de brevet publiés et non publiés sur la BDBC .

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Description du
Document 
Date
(yyyy-mm-dd) 
Nombre de pages   Taille de l'image (Ko) 
Description 1993-10-23 13 576
Dessins 1993-10-23 1 14
Revendications 1993-10-23 3 108
Abrégé 1993-10-23 1 9
Page couverture 1993-10-23 1 16
Taxes 1996-08-19 1 67
Taxes 1995-08-17 1 70
Taxes 1994-08-19 1 72
Taxes 1993-07-12 1 51