Note: Descriptions are shown in the official language in which they were submitted.
0050/46746 CA 02211671 1997-08-13
Solid active ingredient compositions containing hydroxypropyl-
cellulose
5 The present invention relates to solid active ingredient-contain-
ing compositions obtainable by melt extrusion of a mixture of
A) a water-soluble thermoplastic hydroxypropylcellulose,
10 B) one or more active ingredients and
C) if required conventional pharmaceutical ancillary substances,
15 where the content of A) is from 10 to 30% of the total weight of
the mixture.
The invention furthermore relates to a process for producing com-
positions of this type and to drug forms from these compositions.
20 Melt extrusion and its use in pharmaceutical technology is gener-
ally known.
US-A 4 801 460 describes the production of solid drug forms by
melt extrusion of mixtures of active ingredient and thermoplastic
25 N-vinylpyrrolidone polymers.
JP-A 58-79915 and JP-A 58-192817 disclose the production of rod-
shaped drug forms by melt extrusion of water-soluble polymers
such as hydroxypropylcellulose (HPC) or mixtures of HPC with
30 other polymers.
EP-A 596 203 describes active ingredient-containing compositions
which are obtained by mixing the active ingredient with a water-
soluble melt of two polymers which differ in viscosity, for exam-
35 ple polymer mixtures of hydroxypropylcellulose and hydroxypropyl-
methylcellulose.
Active ingredient compositions disclosed to date usually have
relatively high polymer contents. Although high polymer contents
40 result in good processability, the lower active ingredient con-
tents which inevitably result therefrom, that is to say a low
dose of active ingredient with a high tablet weight, may make the
entire production process uneconomic.
45 If, for example, the active ingredient content in a tablet is
originally 40% by weight, for the same dosage the tablet weight
could be halved when the active ingredient content is doubled.
0050/46746
CA 02211671 1997-08-13
Thus, for a given extruder melt output, the production capacity
of the extruder could be doubled.
On the other hand, in the case of active ingredients requiring a
5 low dose, a high active ingredient content would lead to drug
forms whose total weight would be so low that it would be diffi-
cult to handle such a small drug form. However, in such cases, it
would be just as worthwhile to limit the content of the rela-
tively high-cost polymers. In order for the weight of the drug
10 forms not to be less than the reasonable minimum, it would be
worthwhile to replace part of the more costly polymer component
by low-cost, not necessarily meltable ancillary substances.
It is an object of the present invention to find compositions
15 which have a low polymer content while permitting melt processing
of the composition so that the content of active ingredient or
active ingredient and low-cost ancillary substances in the com-
position can be at a maximum.
20 We have found that this object is achieved by the compositions
defined at the outset, and by a process for producing them, and
the use thereof.
The component A) used according to the invention is a water-solu-
25 ble thermoplastic hydroxypropylcellulose which preferably has a
molar degree of substitution of from 3.0 to 4.4. "Molar degree of
substitution" refers to the average number of moles of propylene
oxide which have reacted per glucose unit in the cellulose.
30 The hydroxypropylcellulose can have melt viscosities measured by
the DIN 53735 method in the range from 0.075 to 54.8 g/10 min.
The molecular weight of the hydroxypropylcellulose can vary with-
in wide limits depending on whether slower or faster release of
35 active ingredient is desired. Hydroxypropylcellulose with molecu-
lar weights in the range from 200,000 to 1,500,000 is suitable in
particular for producing drug forms in which 510w release of act-
ive ingredients is desired, since the polymers of higher molecu-
lar weight dissolve less well, and only with swelling, in water.
If, however, it is intended to produce drug forms with faster
release of active ingredient, it is advisable to use polymers of
lower molecular weight which are readily soluble in water, it be-
ing possible in this case to use hydroxypropylcellulose with a
45 molecular weight of from 60,000 to 200,000, preferably 60,000 to
100, 000.
0050/46746 CA 02211671 1997-08-13
The preparation of the hydroxypropylcellulose used according to
the invention is generally known.
The content of hydroxypropylcellulose in the composition is from
5 10 to 30%, preferably 20 to 30%, of the total weight thereof.
Suitable as component B) in the compositions are active ingredi-
ents or mixtures of active ingredients which are thermally stable
under the processing conditions.
Examples of suitable active ingredients according to the inven-
tion are:
acebutolol, acetylcysteine, acetylsalicylic acid, aciclovir,
15 alprazolam, albumin, alfacalcidol, allantoin, allopurinol,
ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, ami-
triptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid,
aspartame, astemizole, atenolol, beclometasone, benserazide,
benzalkonium hydroxide, benzocaine, benzoic acid, betametasone,
20 bezafibrate, biotin, biperiden, bisoprolol, bromazepan, bromhex-
ine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone;
caffeine, camphor, captopril, carbamazepine, carbidopa, carbopla-
tin, ~-carotene and other carotenoids, cefachlor, cefalexin, cefa-
droxil, cefazolin, cefixime, cefotaxime, ceftazidine, ceftriax-
25 one, cefuroxime axetil, chloramphenicol, chlorhexidine, chlorphe-
niramine, chlortalidone, choline, ciclosporin, cilastatin, cime-
tidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, cla-
vulanic acid, clomipramine, clonazepam, clonidine, clotrimazole,
clozapine, codeine, colestyramine, cromoglicic acid, cyanocobala-
30 min, cyproterone desogestrel, dexamethasone, dexpanthenol dextro-
methorphan, dextropropoxiphene, diazepam, diclofenac, digoxin,
dihydrocodeine, dihydroergotamine, diltiazem, diphenhydramine,
dipyridamole, dipyrone, disopyramide, domperidone, dopamine, en-
alapril, ephedrine, epinephrine, ergocalciferol, ergotamine, ery-
35 thromycin, estradiol, ethinylestradiol, etoposide, Eucalyptusglobulus, fam-otidine, felodipine, fenofibrate, fenoterol, fenta-
nyl, flavin mononucleotide, fluconazole, flunarizine, fluoroura-
cil, fluoxetine, flurbiprofen, furosemide, gemfibrozil, gentami-
cin, Ginkgo biloba, glibenclamide, glipizide, Glycyrrhiza glabra,
40 guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochloro-
thiazide, hydrocodone, hydrocortisone, hydromorphon, ipratropium
hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol,
isosorbide dinitrate, isosorbide mononitrate, isotretinoin, keto-
tifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose,
45 lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel,
levothyroxine, lidocaine, lipase, lisinopril, loperamide, loraze-
pam, lovastatin, medroxyprogesterone, menthol, methotrexate, me-
~05U/46'74~
CA 02211671 1997-08-13
thyldopa, methylprednisolone, metoclopramide, metoprolol, micona-
zole, midazolam, minocycline, minoxidil, misoprostol, morphine,
multivitamins and minerals, nystatin, N-methyl-ephedrine, nafti-
drofuril, naproxen, neomycin, nicardipine, nicergoline, nicotina-
5 mide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrendi-
pine, nizatidine, norethisterone, norfloxacin, norgestrel, nor-
triptlyine, ofloxacin, omeprazole, ondansetron, pancreatin, pan-
thenol, pantothenic acid, paracetamol, penicillin G, penicillin
V, phenobarbital, pentoxifylline, phenylephrine, phenylpropanola-
10 mine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravas-
tatin, prazosin, prednisolone, propafenone, propranolol, pseudo-
ephedrine, pyridoxine, quinidine, ramipril, ranitidine, reser-
pine, retinol, riboflavin, rifampicin, rutoside, saccharin, sal-
butamol, salcatonin, salicylic acid, selegiline, simvastatin, so-
15 matotropin, sotalol, spironolactone, sucralfate, sulbactam, sul-
famethoxazole, sulpiride, tamoxifen, tegafur, teprenone, terazo-
sin, terbutaline, terfenadine, theophylline, thiamine, ticlopi-
dine, timolol, tranexamic acid, tretinoin, triamcinolone aceto-
nide, triamterene, trimethoprim, troxerutin, uracil, valproic
20 acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.
Crop protection agents are also suitable as active ingredients.
25 The amount of active ingredient component B) in the complete com-
position may vary within wide limits depending on the activity.
Thus, the content of B) can be from 0.1 to 90~ of the total
weight of the composition.
30 The compositions according to the invention can furthermore con-
tain as components C) conventional pharmaceutical ancillary sub-
stances as long as they are thermally stable under the processing
conditions, eg. fillers or extenders, lubricants, plasticizers,
stabilizers, dyes or pigments, disintegrants, preservatives or
35 flavorings. Examples of suitable fillers are organic compounds
such as lactose or mannitol or inorganic substances such as
silica or silicates, oxides of magnesium, aluminium or titanium.
Fillers which are readily soluble in water, such as lactose or
mannitol, are suitable, for example, for producing compositions
40 with an increased rate of release of active ingredient.
The content of fillers in the composition depends on the dosage
of active ingredient. In the case of active ingredients with low
dosage, it is possible according to the invention to achieve, by
45 higher filler contents, a hlgher tablet weight without adversely
affecting the melt processability. In the case of active ingredi-
0050/46746 CA 02211671 1997-08-13
ents requiring very low doses, the amount of filler can be up to
about 90~ by weight.
Further pharmaceutical ancillary substances which can be used are
5 flow regulators such as mono-, di- and triglycerides of long-
chain fatty acids such as C12-, C14-, C16- and C1g fatty acids or
waxes such as carnauba wax, in the conventional amounts.
Examples of plasticizers which may be mentioned are besides low
10 molecular weight polyalkylene oxides such as polyethylene glycol,
polypropylene glycol and polyethylene/propylene glycol, also
polyhydric alcohols such as propylene glycol, glycerol, pentaery-
thritol and sorbitol, and sodium diethyl sulfosuccinate, glycerol
mono-, di- and triacetate, and polyethylene glycol stearate. In
15 these cases, the amount of plasticizer is about 0.5 to 15, pre-
ferably 0.5 to 5, % by weight.
Examples of lubricants which may be mentioned are stearates of
aluminum or calcium, and talc and silicones, the amount thereof
20 being about 0.1 to 5, preferably 0.1 to 3, ~ by weight.
Examples of stabilizers which may be mentioned are light stabi-
lizers, antioxidants, radical traps and stabilizers against
microbial attack, all of which can be used in conventional
25 amounts.
In order to produce the compositions according to the invention,
the active ingredient component can be either melted directly in
the form of a physical mixture with the polymer A) or mixed with
30 the polymer melt which has already been produced.
Otherwise, the component is mixed with the melt in a conventional
way in extruders, preferably in single or twin screw extruders at
a temperature in the range from 50 to 200 C. The active ingredi-
35 ent-containing polymer melt can be shaped to the compositions
according to the invention for example by calenderinq the extrud-
ate by the method described in EP-A 240 906, and by the proces-
sing method disclosed in DE-A 38 30 335 by comminuting the extru-
date with rotating knives into places of equal volume which are
40 still shapable. The cooled melt can also be processed to gran-
ules.
It is possible to mix the ancillary substances into the melt of
active ingredients and polymer AJ. It is furthermore possible to
45 incorporate the ancillary substances together with the active
ingredient into the polymer melt. It is additionally possible to
melt mixtures of ancillary substances, the active ingredient and
0050/46746 CA 02211671 1997-08-13
the polymer A) directly. It is generally customary to melt a
physical mixture of ancillary substances, active ingredients and
polymers together.
5 The compositions according to the invention are used as drugs in
the form of tablets or granules or employed as pellets in cap-
sules.
If required, the solid pharmaceutical form can also be provided
10 with a conventional coating to improve the appearance and/or
taste (coated tablet) or to reduce the rate of release of active
ingredient.
The present invention makes it possible to produce in a simple
15 manner solid active ingredient compositions by melt extrusion, it
being possible owing to the use of a specific polymer component
to keep the polymer content low without adversely affecting the
melt processability of the composition. It is possible in this
way for a large part of the formulation to consist of active
20 ingredient and low-cost ancillary substances. This makes it pos-
sible for solid drug forms to be produced at particularly reason-
able cost. Particularly in the case of active ingredients requir-
ing low doses it is possible according to the invention to pro-
duce drugs of sizes which are easily handled by melt extrusion of
25 the compositions without the need to use a larger content of the
comparatively high-cost polymer.
Example 1
30 8.0 kg of ambasilide (INN) are extruded with 2.0 kg of a hydroxy-
propylcellulose with a degree of substitution of 3.0-4.4 and a
DIN 53735 melt viscosity of 0.076 g/10 min in a twin screw
extruder (ZSK-40 from ~erner + Pfleiderer, Stuttgart) under the
following conditions:
Shot 1: 90 C
Shot 2: 120 C
Shot 3: 110 C
Shot 4: 110 C
40 Head: 120 C
Dies: 120 C
The throughput was 20 kg/h (weigh feeders). The hard homogeneous
melt was directly compressed to tablets weighing 500 mg in a
45 molding calender located in front of the extruder head.
0050/46746 CA 02211671 1997-08-13
Example 2-
The release of the active ingredient from the tablets from theexample was investigated by the USP XXI paddle method under the
5 following conditions:
- stirrer speed 75 rpm
- release medium simulated gastric fluid (USP) pH 1.0
- temperature 37 C
10 - determination of active ingredient content in the release me-
dium by W spectroscopy
Measured active ingredient release:
Time [min] Active ingredient release
(in [~])
O O
9.0
2030 13.6
17.5
21.1
270 60.0
