HRP960554A2 - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations Download PDF

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Publication number
HRP960554A2
HRP960554A2 HR9523752.5A HRP960554A HRP960554A2 HR P960554 A2 HRP960554 A2 HR P960554A2 HR P960554 A HRP960554 A HR P960554A HR P960554 A2 HRP960554 A2 HR P960554A2
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Croatia
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formulation according
formulation
hydroxypropylmethyl cellulose
molecular weight
polyethylene oxide
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HR9523752.5A
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Croatian (hr)
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Ross James Macrae
Janet Sarah Smith
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Pfizer Res & Dev
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

Ovaj se izum odnosi na oralne farmaceutske formulacije s kontroliranim ispuštanjem. This invention relates to controlled release oral pharmaceutical formulations.

Poznate su oralne farmaceutske formulacije s kontroliranim ispuštanjem. Njihova je svrha da modificiraju brzinu ispuštanja lijeka, na primjer da ostvare konstantnu brzinu ispuštanja nekog lijeka u gastrointestinanalnom traktu pacijenta, ili da odlože ispuštanje nekog lijeka u gastrointestinalnom traktu pacijenta (vidi "Sustained and Controlled Release Drug Delivery Systems", str. 3-6, urednik J.R. Robinson, izdavač Marcel Dekker Ine). Oral pharmaceutical formulations with controlled release are known. Their purpose is to modify the rate of drug release, for example to achieve a constant rate of release of a drug in the patient's gastrointestinal tract, or to delay the release of a drug in the patient's gastrointestinal tract (see "Sustained and Controlled Release Drug Delivery Systems", pp. 3-6 , edited by J.R. Robinson, published by Marcel Dekker Ine).

Američki patent br. 4,765,989, opisuje jednu osmotsku napravu za davanje, između ostalog, nifedipina ili doksazosina. Ona ima perforiran polupropustljiv zid koji obavija ljekovitu kompoziciju koja obuhvaća jedan osmotski polimer, i jednu potiskivačku kompoziciju koja sadrži drugi osmotski polimer. Djelovanje ove poznate naprave je zadovoljavajuće, ali joj je nedostatak to što je veobilo kojemplicirana, što dovodi do velikih proizvodnih troškova. US patent no. 4,765,989, describes an osmotic device for the delivery of, inter alia, nifedipine or doxazosin. It has a perforated semi-permeable wall that encloses a medicinal composition comprising one osmotic polymer, and a pusher composition comprising a second osmotic polymer. The operation of this known device is satisfactory, but its disadvantage is that it is very complicated, which leads to high production costs.

Britanska patentna prijava 2,123,291 prikazuje formulaciju suloktidila s usporenim ispuštanjem koja je dvodijelna tableta: prvi dio je dio trenutnog ispuštanja, dok je drugi dio sporog ispuštanja koji mora sadržavati neko površinski aktivno sredstvo da bi se podstakla biološka erozija. British Patent Application 2,123,291 shows a sustained-release formulation of suloctidyl which is a two-part tablet: the first part is an immediate-release part, while the second part is a slow-release part which must contain some surfactant to promote biological erosion.

Američki patent br. 5,393,765 opisuje erozivnu farmaceutsku kompoziciju koja osigurava profil ispuštanja s kontrolom nultog reda, koja sadrži hidroksipropilmetil celulozu male viskoznosti. US patent no. 5,393,765 describes an erosive pharmaceutical composition that provides a zero-order controlled release profile, containing low viscosity hydroxypropylmethyl cellulose.

Prema prikazanom izumu, ostvarena je farmaceutska kompozicija s kontroliranim ispuštanjem za oralno davanje, koja se u biti sastoji od ljekovitog spoja, polietilen oksida male molekulske mase, hidroksipropilmetil celuloze, dodataka za formiranje tableta i eventualno jednog ili više polimera otpornih na želučane sokove (dalje: enteričkih polimera). According to the presented invention, a pharmaceutical composition with controlled release for oral administration was created, which essentially consists of a medicinal compound, polyethylene oxide of low molecular weight, hydroxypropylmethyl cellulose, additives for forming tablets and possibly one or more polymers resistant to gastric juices (further: enteric polymers).

Prije svega, "oralno davanje" znači davanje u usta praćeno gutanjem. Međutim, formulacija prema prikazanom izumu može se davati i preko usne šupljine (tj. postaviti iza gornje usne i pustiti da se otopi), pa izraz obuhvaća i takve formulacije. First of all, "oral administration" means administration into the mouth followed by swallowing. However, the formulation according to the presented invention can also be administered via the oral cavity (ie, placed behind the upper lip and allowed to dissolve), so the term also includes such formulations.

"Koji se u biti sastoji od" podrazumijeva da je najmanje 95% mas. formulacije načinjeno od navedenih komponenata. Poželjno je da je najmanje 99 % mas. neobloženih formulacija, i jezgri obloženih formulacija načinjeno od navedenih komponenata. "Consisting essentially of" implies that at least 95% by weight. formulations made from the above components. It is desirable that at least 99% by mass. uncoated formulations, and coated formulation cores made of the above components.

Polimeriziran etilen oksid koji ima brojčanu prosječnu molekulsku masu manju od 100 000 ponekad se spominje kao "polietilen glikol". Međutim, radi pojednostavljenja, izraz "polietilen oksid male molekulske težine" se koristi za označavanje polimeriziranog etilen oksida u opsegu brojčane prosječne molekulske mase koji je interesantan, i to od 15000 do 750000. Polymerized ethylene oxide having a number average molecular weight of less than 100,000 is sometimes referred to as "polyethylene glycol". However, for simplicity, the term "low molecular weight polyethylene oxide" is used to refer to polymerized ethylene oxide in the number average molecular weight range of interest, namely 15,000 to 750,000.

Inertni dodaci za formiranje tableta koji dopunjuju formulaciju prema izumu, mogu biti konvencionalni inertni dodaci za tablete kao, na primjer, dvobazni kalcij fosfat, laktoza i magnezij stearat. Inert tablet forming additives supplementing the formulation according to the invention may be conventional inert tablet additives such as, for example, dibasic calcium phosphate, lactose and magnesium stearate.

Postoje tri klase ljekovitih spojeva posebno pogodnih za davanje u formulacijama prema izumu. Prva klasa su slabo bazni spojevi. Primjeri te klase obuhvaćaju dipiridamol, noskapin, papaverin, doksazosin, sildenafil i prazosin. Doksazosin i njegove farmaceutski prihvatljive soli su posebno interesantni. There are three classes of medicinal compounds particularly suitable for administration in the formulations of the invention. The first class are weakly basic compounds. Examples of this class include dipyridamole, noscapine, papaverine, doxazosin, sildenafil and prazosin. Doxazosin and its pharmaceutically acceptable salts are of particular interest.

Drugu klasu čine spojevi velike topivosti u vodenim sredinama. Primjeri ove klase obuhvaćaju salbutamol, metoprolol, propanolol, aminofilin, izosorbid mononitrat i dinitrat, gliceril trinitrat, verapamil, kaptopril, diltiazem, morhin, hlorfeniramin, prometazin eletriptan, darifenacin i flukonazol. The second class consists of compounds with high solubility in water environments. Examples of this class include salbutamol, metoprolol, propanolol, aminophylline, isosorbide mononitrate and dinitrate, glyceryl trinitrate, verapamil, captopril, diltiazem, morphine, chlorpheniramine, promethazine eletriptan, darifenacin, and fluconazole.

Treću klasu čine spojevi male topivosti u vodenim sredinama. Primjeri te klase obuhvaćaju nifedipin, grizeofulvin, karbamazepin, felodipin, nimodipin i megestrol. The third class consists of compounds with low solubility in water environments. Examples of this class include nifedipine, griseofulvin, carbamazepine, felodipine, nimodipine and megestrol.

Stručnjaci znaju značenje izraza "velika topivost u vodenim sredinama" i "mala topivost u vodenim sredinama". Ipak, prva se može definirati kao topivost > 1 mg/ml u vodi, a druga se može definirati kao topivost <1 mg/ml u vodi. Experts know the meaning of the terms "high solubility in aqueous environments" and "low solubility in aqueous environments". However, the first can be defined as solubility > 1 mg/ml in water, and the second can be defined as solubility <1 mg/ml in water.

Stručnjacima će biti jasno da neki od spojeva mogu spadati u više od jedne od navedenih klasa, pa tako, na primjer, neki spojevi mogu biti slabo bazni i da imati veliku topivost u vodenim sredinama. It will be clear to those skilled in the art that some of the compounds may fall into more than one of the listed classes, so, for example, some compounds may be weakly basic and have high solubility in aqueous environments.

Formulacije prema izumu imaju tu prednost da osiguravaju konstantnu brzinu ispuštanja lijekova koji su slabo bazni i/ili velike topivosti u vodenim sredinama u in vitro modelima gastrointestinalnog trakta, pa se očekuje da osiguraju konstantnu brzinu ispuštanja lijeka i u gastrointestinalnom traktu pacijenta. Formulations according to the invention have the advantage of ensuring a constant rate of release of drugs that are weakly basic and/or highly soluble in aqueous media in in vitro models of the gastrointestinal tract, so they are expected to provide a constant rate of drug release in the patient's gastrointestinal tract as well.

Kada lijek koji se treba dati ima malu topivost u vodenim sredinama, formulacije prema izumu imaju tu prednost da proizvode odloženo ili impulsno ispuštanje lijeka. U svakom slučaju, formulacije su veoma jednostavne pa se mogu proizvoditi uz razmjerno male troškove. When the drug to be administered has a low solubility in aqueous media, the formulations according to the invention have the advantage of producing a delayed or pulsed release of the drug. In any case, the formulations are very simple, so they can be produced at relatively low costs.

Pogodno je da hidroksipropilmetil celuloza ima brojčanu prosječnu molekulsku masu u opsegu 80000-250000. Pogodno je da hidroksipropilmetil celuloza ima stupanj metil supstitucije u opsegu 19-30%. Pogodno je da hidroksipropilmetil celuloza ima stupanj hidroksi supstitucije u opsegu 4-12%. Više polimera hidroksipropilmetil celuloze može se naći na tržištu pod zaštićenim nazivom Methocel® a neki od njih, pogodni za primjenu u formulacijama prema izumu dati su u slijedećoj tabeli: Suitably, the hydroxypropylmethyl cellulose has a number average molecular weight in the range of 80,000-250,000. It is convenient for the hydroxypropylmethyl cellulose to have a degree of methyl substitution in the range of 19-30%. It is convenient for the hydroxypropylmethyl cellulose to have a degree of hydroxy substitution in the range of 4-12%. Several hydroxypropylmethyl cellulose polymers can be found on the market under the trade name Methocel®, and some of them, suitable for use in the formulations according to the invention, are given in the following table:

[image] [image]

Methocel® K4M ima karakteristike koje su od posebnog interesa. Methocel® K4M has characteristics that are of particular interest.

Pogodno je da polietilen oksid male molekulske mase ima brojčanu prosječnu molekulsku masu u opsegu od 10000 do 500000, poželjnije 100000-300000. Suitably, the low molecular weight polyethylene oxide has a number average molecular weight in the range of 10,000 to 500,000, more preferably 100,000 to 300,000.

Polietilen oksid s brojčanom prosječnom molekulskom masom iznad 100 000 je prašak, što ga čini lakšim za rukovanje od polietilen oksida manje molekulske mase, koji ima nižu točku topljenja. Tako, na primjer, polietilen oksid s brojčanom prosječnom molekulskom masom od 6000 ima točku topljenja od 60-63°C. Polyethylene oxide with a number average molecular weight above 100,000 is a powder, which makes it easier to handle than lower molecular weight polyethylene oxide, which has a lower melting point. Thus, for example, polyethylene oxide with a number average molecular weight of 6000 has a melting point of 60-63°C.

Stručnjacima će biti jasno da se polietilen oksid može sastojati od molekula različitih dužina niza, ali da prosječna dužina niza daje molekulsku masu u naznačenom opsegu. Isto važi i za hidroksipropilmetil celulozu. It will be clear to those skilled in the art that polyethylene oxide can consist of molecules of varying chain lengths, but that the average chain length gives a molecular weight in the indicated range. The same applies to hydroxypropylmethyl cellulose.

Formulacije prema izumu mogu sadržati neki enterički polimer pomiješan s drugim komponentama formulacije. Pored toga, ili alternativno, formulacije prema izumu su poželjno izvedene s oblogom od nekog enteričnog polimera. Enterički polimeri koji se mogu spomenuti jesu derivati ftalata (uključujući ftalat acetata celuloze, polivinilacetat ftalat i ftalat hidroksipropilmetil celuloze), i vinil acetat i kopolimeri krotonske kiseline. Kopolimer metakrilne kiseline je od posebnog interesa. Formulations according to the invention may contain some enteric polymer mixed with other components of the formulation. In addition, or alternatively, the formulations according to the invention are preferably made with a coating of an enteric polymer. Enteric polymers that may be mentioned are phthalate derivatives (including cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxypropylmethyl cellulose phthalate), and vinyl acetate and crotonic acid copolymers. Methacrylic acid copolymer is of particular interest.

Pogodno je da formulacija sadrži do oko 50% mas. aktivnog ljekovitog spoja, na primjer 1-20%. It is convenient for the formulation to contain up to about 50% by weight. of the active medicinal compound, for example 1-20%.

Preporučljivo je da formulacija prema izumu sadrži 5-30% mas. poli etilen oksida male molekulske mase, na primjer 8-10%. It is recommended that the formulation according to the invention contains 5-30% wt. polyethylene oxide of low molecular weight, for example 8-10%.

Pogodno je da formulacija prema izumu sadrži 10-60% mas. hidroksipropilmetil celuloze, na primjer 25-35%. It is convenient that the formulation according to the invention contains 10-60% by weight. hydroxypropylmethyl cellulose, for example 25-35%.

Formulacije koje imaju enterički polimer pomiješan s drugim komponentama formulacije, imaju, poželjno, 10-40% mas. pomiješanog enteričkog polimera, na primjer 25-35%. Formulations having an enteric polymer mixed with other formulation components preferably have 10-40% by weight. of mixed enteric polymer, for example 25-35%.

Kod formulacija prema prikazanom izumu pogodno je da odnos masa polietilen oksida male molekulske mase i hidroksiprolipmetil celuloze bude u opsegu od 2:1 -1:5. In the case of formulations according to the presented invention, it is suitable for the mass ratio of polyethylene oxide of low molecular weight and hydroxyprolipmethyl cellulose to be in the range of 2:1-1:5.

U formulacijama prema prikazanom izumu koje sadrže pomiješan enterički polimer, pogodno je da odnos masa (polietilen oksid male molekulske mase + hidroksipropilmetil celuloza) : dodan enterički polimer bude u opsegu 1:2-6:1, poželjnije 1:2-2:1. Pogodno je da enterička obloga (kada je ima) iznosi 2-15% mas. formulacije, pogodnije 5-10 % mas. formulacije. In the formulations according to the presented invention that contain a mixed enteric polymer, it is convenient that the mass ratio (polyethylene oxide of low molecular weight + hydroxypropylmethyl cellulose) : added enteric polymer is in the range of 1:2-6:1, more preferably 1:2-2:1. It is convenient that the enteric lining (when present) amounts to 2-15% by weight. formulations, more suitable 5-10 % wt. formulations.

Prema jednom drugom obliku izuma, ostvarena je primjena polietilen oksida male molekulske mase u oralnoj farmaceutskoj formulaciji s kontroliranim ispuštanjem, koja ima matricu od hidroksipropilmetil celuloze, radi ubrzanja erozije matrice nakon nekog određenog perioda vremena nakon davanja formulacije pacijentu. According to another form of the invention, the application of polyethylene oxide of low molecular weight in an oral pharmaceutical formulation with controlled release, which has a matrix of hydroxypropylmethyl cellulose, was achieved in order to accelerate erosion of the matrix after a certain period of time after administration of the formulation to the patient.

Obično je taj unaprijed određen period vremena 6 sati. Na taj se način može postići konstantna brzina ispuštanja lijeka u gastrointestinalnom traktu pacijenta, unatoč promjenjivim uvjetima koji se javljaju njegovom dužinom. Usually, this predetermined period of time is 6 hours. In this way, a constant rate of drug release can be achieved in the patient's gastrointestinal tract, despite the changing conditions that occur along its length.

Mijenjanjem udijela polietilenoksida u formulaciji, moguće je regulirati početak ubrzanja erozije matrice a time i početak povećanog ispuštanja lijeka nakon davanja formulacije pacijentu. By changing the proportion of polyethylene oxide in the formulation, it is possible to regulate the onset of accelerated erosion of the matrix and thus the onset of increased drug release after administration of the formulation to the patient.

Prema još jednom obliku izuma, ostvaren je postupak za proizvodnju farmaceutske formulacije, kako je definirana u zahtijevu l, koja obuhvaća miješanje aktivnog ljekovitog spoja, polietilen oksida male molekulske mase, hidroksipropilmetil celuloze, inertnih dodataka za formiranje tablete, i eventualno jednog ili više enetričkih polimera, i zatim prešanje u tablete. According to another form of the invention, a process for the production of a pharmaceutical formulation, as defined in claim 1, has been achieved, which includes the mixing of an active medicinal compound, polyethylene oxide of low molecular weight, hydroxypropylmethyl cellulose, inert additives for tablet formation, and possibly one or more enetic polymers , and then pressing into tablets.

Svojstva ispuštanja lijeka formulacija prema prikazanom izumu mogu se mjeriti u modelu gastrointestinalnog trakta kao što je Uređaj l (Apparatus 1) 22. izdanja Farmakopeje SAD (USP 22), strana 1578, Postupak l (korpice) [Method l (baskets)]. The drug release properties of the formulations according to the present invention can be measured in a model of the gastrointestinal tract such as Apparatus 1 (Apparatus 1) of the 22nd edition of the US Pharmacopoeia (USP 22), page 1578, Method 1 (baskets) [Method 1 (baskets)].

Izum je ilustriran slijedećim primjerima s pozivom na priložene crteže, gdje The invention is illustrated by the following examples with reference to the accompanying drawings, where

slika 1 prikazuje postotak ispuštenog ljekovitog spoja u funkciji vremena iz formulacija prema izumu [pripremljenih u Primjerima 1 (a) i 1(b)] u usporedbi s kontrolnom formulacijom [pripremljenom u Primjeru 6] koristeći jednostavno ispitivanje otapanjem, a Figure 1 shows the percentage of drug compound released as a function of time from the formulations of the invention [prepared in Examples 1(a) and 1(b)] compared to the control formulation [prepared in Example 6] using a simple dissolution test, and

slika 2 prikazuje postotak ispuštenog ljekovitog spoja u funkciji vremena iz jedne formulacije prema izumu [pripremljene u Primjeru 2(a)] koristeći ispitivanje otapanjem prvo s jednim kiselinskim, a zatim neutralnim medijem za otapanje. Figure 2 shows the percentage of drug compound released as a function of time from a formulation according to the invention [prepared in Example 2(a)] using a dissolution test first with an acidic and then a neutral dissolution medium.

Primjer 1 Example 1

Formulacije doksazosin mesilata zadržanog ispuštanja Sustained release formulations of doxazosin mesylate

(a) (And)

[image] [image]

a ekvivalentno 3 mg doksazosina na bazi teorijske aktivnosti od 82,5% and equivalent to 3 mg of doxazosin based on a theoretical activity of 82.5%

b kaoPolyox®WSRN10 b as Polyox®WSRN10

c kao Polyox® WSR N 80 c as Polyox® WSR N 80

d kao Methoce1® K4M d as Methoce1® K4M

e kao bezvodni e as anhydrous

f kao laktoza fast flo. f as lactose fast flo.

Svi su sastojci osim magnezij stearata miješani zajedno u jednoj Turbula miješalici u trajanju od 10 minuta. Smjesa je zatim prosijana koristeći sito od 30 mesh-a (otvori od 500 μm) i ponovo miješani slijedećih 10 minuta. Zatim je magnezij stearat prosejan kroz sito od 30 mesh-a (otvori od 500 μm) pa je dodan smjesi i sve je miješano još 5 minuta, Smjesa je komprimirana na stroju za izradu tableta koristeći normalne okrugle konveksne alate da bi se načinio traženi broj tableta od mase od 200 mg. All ingredients except magnesium stearate were mixed together in a Turbula mixer for 10 minutes. The mixture was then sieved using a 30 mesh sieve (500 μm openings) and mixed again for a further 10 minutes. Magnesium stearate was then sieved through a 30 mesh sieve (500 μm openings) and added to the mixture and mixed for another 5 minutes. The mixture was compressed on a tablet machine using normal round convex tools to make the required number of tablets. from a mass of 200 mg.

(b) (b)

[image] [image]

a ekvivalentno 4 mg doksazosina na bazi teorijske aktivnosti od 82,5% and equivalent to 4 mg of doxazosin based on a theoretical activity of 82.5%

b kao Polyox® VVSR N 10 b as Polyox® VVSR N 10

c kao Polyox® VVSR N 80 c as Polyox® VVSR N 80

d kao Methocel® K4M d as Methocel® K4M

e kao bezvodni e as anhydrous

f kao laktoza fast flo. f as lactose fast flo.

Pripremljeno je 200 mg tableta prema postupku iz (a), 200 mg tablets were prepared according to the procedure from (a),

(c) (c)

[image] [image]

a ekvivalentno 4 mg doksazosina na bazi teorijske aktivnosti od 82,5% and equivalent to 4 mg of doxazosin based on a theoretical activity of 82.5%

b kao Polyox® VVSR N 10 b as Polyox® VVSR N 10

c kao Polyox® VVSR N 80 c as Polyox® VVSR N 80

d kao Methocel® K4M d as Methocel® K4M

e kao bezvodni e as anhydrous

f kao laktoza fast flo. f as lactose fast flo.

Pripremljeno je 200 mg tableta prema postupku iz (a). 200 mg tablets were prepared according to the procedure from (a).

Primjer 2 Example 2

Formulacije doksazosin mesilata zadržanog ispuštanja koje sadrže jedan enterički polimer Sustained-release formulations of doxazosin mesylate containing an enteric polymer

(a) (And)

[image] [image]

a ekvivalentno 3 mg doksazosina na bazi teorijske aktivnosti od 82,5% and equivalent to 3 mg of doxazosin based on a theoretical activity of 82.5%

b kao Polyox® WSR N 10 b as Polyox® WSR N 10

c kao Polyox® WSR N 80 c as Polyox® WSR N 80

d kao Methocel® K4M d as Methocel® K4M

e kao Eudragit® L 100 55 e as Eudragit® L 100 55

f kao bezvodni f as anhydrous

g kao laktoza fast flo. g as lactose fast flo.

Pripremljeno je 200 mg tableta prema postupku iz Primjera 1 (a). 200 mg tablets were prepared according to the procedure from Example 1 (a).

(b) (b)

[image] [image]

a ekvivalentno 4 mg doksazosina na bazi teorijske aktivnosti od 82,5% and equivalent to 4 mg of doxazosin based on a theoretical activity of 82.5%

b kaoPolyox®WSRN10 b as Polyox®WSRN10

c kaoPolyox®WSRN80 c as Polyox®WSRN80

d kao Methocel® K4M d as Methocel® K4M

e kao Eudragit® L 10055 e as Eudragit® L 10055

f kao bezvodni f as anhydrous

g kao laktoza fast flo. g as lactose fast flo.

Pripremljeno je 200 mg tableta prema postupku iz Primjera l (a). 200 mg tablets were prepared according to the procedure from Example 1 (a).

Primjer 3 Example 3

Formulacije doksazosin mesilata koje imaju enteričku oblogu Formulations of doxazosin mesylate that have an enteric coating

(a) (And)

[image] [image]

a kao Eudragit® L 100-55 and as Eudragit® L 100-55

b gubi se u tijeku obrade i ne javlja se u gotovom proizvodu. b is lost during processing and does not appear in the finished product.

Svi su sastojci osim tableta miješani sve dok kopolimer metakrilne kiseline nije bio disperziran. Smjesa je zatim nanijeta na tablete raspršivanjem da bi se dobila obloga potrebne mase koristeći uobičajen postupak. All ingredients except the tablets were mixed until the methacrylic acid copolymer was dispersed. The mixture was then sprayed onto the tablets to obtain a coating of the required mass using a conventional process.

(b) (b)

[image] [image]

a kao Eudragit® L 100-55 and as Eudragit® L 100-55

b gubi se u tijeku obrade i ne javlja se u gotovom proizvodu. b is lost during processing and does not appear in the finished product.

Tablete su bile obložene prema postupku iz (a), (c) The tablets were coated according to the procedure from (a), (c)

[image] [image]

a kao Eudragit® L 100 and as Eudragit® L 100

b kao Eudragit® S 100 b as Eudragit® S 100

c Otopina amonijaka gustoće 0,91 (25% NH3). Vodena komponenta te otopine gubi se tijekom obrade. c Ammonia solution with a density of 0.91 (25% NH3). The aqueous component of this solution is lost during processing.

d Gubi se tijekom obrade i ne javlja se u gotovom proizvodu. d It is lost during processing and does not appear in the finished product.

Tablete su bile obložene prema postupku iz (a). The tablets were coated according to the procedure from (a).

Primjer 4 Example 4

Formulacija darifenacin hidrobromida sa zadržanim ispuštanjem Sustained release formulation of darifenacin hydrobromide

[image] [image]

[image] [image]

a ekvivalentno 30 mg darifenacina na bazi teorijske aktivnosti od 84% and equivalent to 30 mg of darifenacin based on a theoretical activity of 84%

b kao Polyox®WSRN10 b as Polyox®WSRN10

c kao Polyox®WSRN80 c as Polyox®WSRN80

d kao Methocel® K4M d as Methocel® K4M

e kao laktoza fast flo. e like lactose fast flo.

Pripremljeno je 200 mg tableta prema postupku iz Primjera 1 (a). 200 mg tablets were prepared according to the procedure from Example 1 (a).

Primjer 5 Example 5

Formulacije flukonazola zadržanog ispuštanja (pogodne za davanje kroz usnu šupljinu) Sustained release formulations of fluconazole (suitable for oral administration)

(a) (And)

[image] [image]

a kao Polyox®WSRN10 and as Polyox®WSRN10

b kao Polyox®WSRN80 b as Polyox®WSRN80

c kao Methocel® K4M c as Methocel® K4M

d kao laktoza fast flo. d as lactose fast flo.

Pripremljeno je 100 mg tableta prema postupku iz Primjera 1 (a), 100 mg tablets were prepared according to the procedure from Example 1 (a),

(b) (b)

[image] [image]

a kao Polyox®WSRN10 and as Polyox®WSRN10

b kao Methocel® K4M b as Methocel® K4M

c kao bezvodni. c as anhydrous.

Pripremljeno je 100 mg tableta prema postupku iz Primjera 1(a). 100 mg tablets were prepared according to the procedure of Example 1(a).

Primjer 6 (uporedni) Example 6 (comparative)

Formulacija doksazosin mesilata zadržanog ispuštanja bez polietilenoksida Doxazosin mesylate sustained-release formulation without polyethylene oxide

(a) (And)

[image] [image]

a ekvivalentno 3 mg doksazosina na bazi teorijske aktivnosti od 82,5% and equivalent to 3 mg of doxazosin based on a theoretical activity of 82.5%

b kao Methocel® K4M b as Methocel® K4M

c kao bezvodni c as anhydrous

d kao laktoza fast flo. d as lactose fast flo.

Pripremljeno je 200 mg tableta prema postupku iz Primjera l (a). 200 mg tablets were prepared according to the procedure from Example 1 (a).

Primjer 7 Example 7

Analiza otapanja Dissolution analysis

Tablete iz Primjera l (a). 1(b) i 6 otopine su koristeći Uređaj 1 (Apparatus 1) 22. izdanja Farmakopeje SAD (USP 22), strana 1578, Postupak 1 (korpice) [Method l (baskets)]. Fluid za otapanje je bio 900 ml vode na 37°C, brzina okretanja korpica bila je 100 min-1, a oslobođeno ljekoviti spoj otkriveno je UV spektroskopijom na valnoj dužini od 246 nm. Postotak ispuštenog ljekovitog spoja u funkciji vremena za svaku vrstu tableta prikazan je na slici 1. Tablets from Example 1 (a). 1(b) and 6 were dissolved using Apparatus 1 (Apparatus 1) of the 22nd edition of the United States Pharmacopoeia (USP 22), page 1578, Method 1 (baskets) [Method 1 (baskets)]. The dissolution fluid was 900 ml of water at 37°C, the basket rotation speed was 100 min-1, and the released medicinal compound was detected by UV spectroscopy at a wavelength of 246 nm. The percentage of released medicinal compound as a function of time for each type of tablet is shown in Figure 1.

Tablete iz Primjera 2 otopljene su koristeći Uređaj 1 (Apparatus 1) 22. izdanja Farmakopeje SAD (USP 22), strana 1578, Postupak 1 (korpice) [Method 1 (baskets)]. Fluid za otapanje je bio 900 ml kiselog medija [1M HC1, 100 ml; NaCl, 70,2 g; vode do 10 1; pH=2] na 37°C tijekom 2 sata, koji je zamijenjen medijem s neutralnim pH [KH2PO4, 8,7 g; KCl, 47,4 g; NaCl, 20,3 g; 1M NaOH 52 ml; vode do 10 1] koji je korišten u preostalom dijelu pokusa. Brzina okretaja korpica bila je 200 min-1, a oslobođeno ljekoviti spoj otkriven je UV spektroskopijom na valnoj dužini od 246 nm. Postotak ispuštenog ljekovitog spoja u funkciji vremena prikazanje na slici 2. The tablets of Example 2 were dissolved using Apparatus 1 (Apparatus 1) of the 22nd edition of the United States Pharmacopoeia (USP 22), page 1578, Method 1 (baskets). The dissolution fluid was 900 ml of acidic medium [1M HCl, 100 ml; NaCl, 70.2 g; water up to 10 1; pH=2] at 37°C for 2 hours, which was replaced by neutral pH medium [KH2PO4, 8.7 g; KCl, 47.4 g; NaCl, 20.3 g; 1M NaOH 52 ml; of water up to 10 1] which was used in the remaining part of the experiment. The speed of rotation of the baskets was 200 min-1, and the released medicinal compound was detected by UV spectroscopy at a wavelength of 246 nm. The percentage of released medicinal compound as a function of time is shown in Figure 2.

Claims (25)

1. Farmaceutska formulacija s kontroliranim ispuštanjem za oralno davanje, naznačena time, što se sastoji, u biti, od aktivnog ljekovitog spoja, polietilen oksida male molekulske mase, hidroksipropilmetil celuloze, inertnih dodataka za formiranje tableta i, eventualno, jednog ili više enteričkih polimera.1. A controlled-release pharmaceutical formulation for oral administration, characterized in that it consists essentially of an active medicinal compound, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, inert tablet-forming additives and, optionally, one or more enteric polymers. 2. Formulacija prema zahtjevu 1, naznačena time, što je aktivni ljekoviti spoj slabo bazni,2. Formulation according to claim 1, indicated by the fact that the active medicinal compound is weakly basic, 3. Formulacija prema zahtjevu 1 ili 2, naznačena time, što je aktivni ljekoviti spoj doksazosin ili neka njegova farmaceutski prihvatljiva sol.3. Formulation according to claim 1 or 2, characterized in that the active medicinal compound is doxazosin or a pharmaceutically acceptable salt thereof. 4. Formulacija prema zahtjevu 1, naznačena time, što aktivni ljekovito spoj ima veliku topivost u vodenim sredinama.4. Formulation according to claim 1, characterized in that the active medicinal compound has high solubility in aqueous media. 5. Formulacija prema zahtjevu 1, naznačena time, što aktivni ljekoviti spoj ima malu topivost u vodenim sredinama.5. Formulation according to claim 1, characterized in that the active medicinal compound has a low solubility in aqueous media. 6. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što hidroksipropilmetil celuloza ima brojčanu prosječnu molekulsku masu u opsegu od 80 000 do 250 000.6. The formulation according to any one of the preceding claims, characterized in that the hydroxypropylmethyl cellulose has a number average molecular weight in the range of 80,000 to 250,000. 7. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što hidroksipropilmetil celuloza ima stupanj metil supstitucije u opsegu od 19-30%.7. The formulation according to any of the preceding claims, characterized in that the hydroxypropylmethyl cellulose has a degree of methyl substitution in the range of 19-30%. 8. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što hidroksipropilmetil celuloza ima stupanj hidroksi supstitucije u opsegu od 19-30%.8. Formulation according to any of the preceding claims, characterized in that the hydroxypropylmethyl cellulose has a degree of hydroxy substitution in the range of 19-30%. 9. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što polietilen oksid ima brojčanu prosječnu molekulsku masu u opsegu od 20 000 do 500 000.9. The formulation according to any of the preceding claims, characterized in that the polyethylene oxide has a number average molecular weight in the range of 20,000 to 500,000. 10. Formulacija prema zahtjevu 9, naznačena time, što polietilen oksid ima brojčanu prosječnu molekulsku masu u opsegu od 100 000 do 300 000.10. Formulation according to claim 9, characterized in that the polyethylene oxide has a number average molecular weight in the range of 100,000 to 300,000. 11. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što je jedan enterički polimer pomiješan s drugim komponentama formulacije.11. Formulation according to any of the preceding claims, characterized in that one enteric polymer is mixed with other components of the formulation. 12. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što ima oblogu koja sadrži neki enterički polimer.12. A formulation according to any of the preceding claims, characterized in that it has a coating containing an enteric polymer. 13. Formulacija prema zahtjevu 11 ili 12, naznačena time, što je enterički polimer kopolimer metakrilne kiseline.13. Formulation according to claim 11 or 12, characterized in that the enteric polymer is a copolymer of methacrylic acid. 14. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što sadrži do 50% mas. aktivnog ljekovitog spoja.14. The formulation according to any of the preceding claims, characterized by the fact that it contains up to 50% by weight. active medicinal compound. 15. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što sadrži do 5-30% mas. polietilen oksida.15. The formulation according to any of the preceding claims, characterized in that it contains up to 5-30% by weight. polyethylene oxide. 16. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što sadrži do 10-60% mas. hidroksipropilmetil celuloze.16. The formulation according to any of the preceding claims, characterized in that it contains up to 10-60% by weight. hydroxypropylmethyl cellulose. 17. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što sadrži do 10-40% mas. enteričkog polimera pomiješanog s drugim komponentama formulacije.17. The formulation according to any of the preceding claims, characterized in that it contains up to 10-40% by weight. of enteric polymer mixed with other formulation components. 18. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što je odnos masa polietilen oksida male molekulske mase i hidroksipropilmetil celuloze u opsegu 2:1-1:5.18. The formulation according to any of the previous requirements, indicated by the fact that the mass ratio of polyethylene oxide of low molecular weight and hydroxypropylmethyl cellulose is in the range of 2:1-1:5. 19. Formulacija prema bilo kojem od prethodnih zahtijeva, naznačena time, što je odnos masa polietilen oksida male molekulske mase + hidroksipropilmetil celuloze i dodanog enteričkog polimera u opsegu 1.2-6:1.19. Formulation according to any of the previous requirements, indicated by the fact that the mass ratio of low molecular weight polyethylene oxide + hydroxypropylmethyl cellulose and added enteric polymer is in the range of 1.2-6:1. 20. Formulacija prema zahtjevu 19, naznačena time, što je odnos masa polietilen oksida male molekulske mase + hidroksipropilmetil celuloze i dodanog enteričkog polimera u opsegu 1:2-2:1.20. Formulation according to claim 19, characterized in that the mass ratio of low molecular weight polyethylene oxide + hydroxypropylmethyl cellulose and added enteric polymer is in the range of 1:2-2:1. 21. Formulacija prema bilo kojem od zahtijeva 12-20, naznačena time, što enterička obloga sačinjava 2-15% mas. formulacije.21. The formulation according to any one of claims 12-20, characterized in that the enteric coating constitutes 2-15% by weight. formulations. 22. Formulacija prema zahtjevu 21, naznačena time, što enterička obloga sačinjava 5-10% mas. formulacije.22. Formulation according to claim 21, characterized in that the enteric coating constitutes 5-10% by weight. formulations. 23. Primjena polietilen oksida male molekulske mase kod oralne farmaceutske formulacije s kontroliranim ispuštanjem, koja ima matricu od hidroksipropilmetil celuloze, radi pospješivanja erozije matrice nakon unaprijed određenog vremenskog perioda nakon davanja formulacije pacijentu.23. Use of low molecular weight polyethylene oxide in a controlled release oral pharmaceutical formulation having a matrix of hydroxypropylmethyl cellulose to promote erosion of the matrix after a predetermined period of time after administration of the formulation to a patient. 24. Primjena prema zahtjevu 23, naznačena time, što je unaprijed određeni period vremena 6 sati.24. Application according to claim 23, characterized in that the predetermined period of time is 6 hours. 25. Postupak za proizvodnju farmaceutske formulacije kako je definirana u zahtjevu 1, naznačen time, što obuhvaća miješanje aktivnog ljekovitog spoja, polietilen oksida male molekulske mase, hidroksipropilmetil celuloze, inertnih dodataka za formiranje tableta i, eventualno, jednog ili više enteričkih polimera, a zatim prešanje u tablete.25. A process for the production of a pharmaceutical formulation as defined in claim 1, indicated by the fact that it comprises the mixing of an active medicinal compound, polyethylene oxide of low molecular weight, hydroxypropylmethyl cellulose, inert additives for forming tablets and, possibly, one or more enteric polymers, and then pressing into tablets.
HR9523752.5A 1995-11-21 1996-11-21 Pharmaceutical formulations HRP960554A2 (en)

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