SE538425C2 - Pharmaceutical compositions comprising levodopa, carbidopa and a comt inhibitor and method of administration thereof - Google Patents

Pharmaceutical compositions comprising levodopa, carbidopa and a comt inhibitor and method of administration thereof Download PDF

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Publication number
SE538425C2
SE538425C2 SE1451034A SE1451034A SE538425C2 SE 538425 C2 SE538425 C2 SE 538425C2 SE 1451034 A SE1451034 A SE 1451034A SE 1451034 A SE1451034 A SE 1451034A SE 538425 C2 SE538425 C2 SE 538425C2
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Sweden
Prior art keywords
gel composition
levodopa
carbidopa
composition according
pharmaceutical
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SE1451034A
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Swedish (sv)
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SE1451034A1 (en
Inventor
Roger Bolsöy
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Lobsor Pharmaceuticals Ab
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Priority to SE1451034A priority Critical patent/SE538425C2/en
Priority to HRP20240314TT priority patent/HRP20240314T1/en
Priority to RS20240276A priority patent/RS65337B1/en
Priority to ES20200070T priority patent/ES2973289T3/en
Priority to SI201531992T priority patent/SI3782617T1/en
Priority to US15/507,959 priority patent/US10071069B2/en
Priority to PT158388009T priority patent/PT3188725T/en
Priority to FIEP20200070.9T priority patent/FI3782617T3/en
Priority to AU2015312430A priority patent/AU2015312430B2/en
Priority to HUE15838800A priority patent/HUE052857T2/en
Priority to PT202000709T priority patent/PT3782617T/en
Priority to EP23219005.8A priority patent/EP4356907A1/en
Priority to CA3175785A priority patent/CA3175785A1/en
Priority to CN201580050984.7A priority patent/CN107072973A/en
Priority to PCT/SE2015/050939 priority patent/WO2016036308A1/en
Priority to PL15838800T priority patent/PL3188725T3/en
Priority to EP15838800.9A priority patent/EP3188725B1/en
Priority to JP2017533154A priority patent/JP6622310B2/en
Priority to DK20200070.9T priority patent/DK3782617T3/en
Priority to EP20200070.9A priority patent/EP3782617B1/en
Priority to CA2959307A priority patent/CA2959307C/en
Priority to ES15838800T priority patent/ES2844500T3/en
Priority to SI201531474T priority patent/SI3188725T1/en
Priority to DK15838800.9T priority patent/DK3188725T3/en
Publication of SE1451034A1 publication Critical patent/SE1451034A1/en
Publication of SE538425C2 publication Critical patent/SE538425C2/en
Priority to US16/054,392 priority patent/US10786472B2/en
Priority to JP2019210309A priority patent/JP6889231B2/en
Priority to US16/992,824 priority patent/US11413262B2/en
Priority to AU2020239682A priority patent/AU2020239682B2/en
Priority to HRP20210025TT priority patent/HRP20210025T1/en
Priority to AU2022200291A priority patent/AU2022200291B2/en
Priority to US17/834,839 priority patent/US20220362193A1/en

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

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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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

22 Abstract A pharrnaceutical gel composition for intestinal administration comprises at least10 Ing/ml of levodopa, at least 2,5 mg/ml of carbidopa, and at least 10 mg/ml of aCOMT inhibitor Wherein the COMT inhibitor is entacapone.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING LEVODOPA, CARBIDOPAAND A COMT INHIBITOR AND METHOD OF ADMINISTRATION THEREOF Field of the invention The present invention relates to novel pharmaceutical compositions comprisinglevodopa, carbidopa and a COMT inhibitor, such as entacapone, orpharmaceutically acceptable salts or hydrates thereof. The invention also relates to a method of administration of such compositions.
Background of the invention Parkinson's disease (PD) is a neurodegenerative disorder characterized by aprogressive degeneration of the dopaminergic pathWay resulting in reducedconcentration of the neurotransmitter dopamine in the brain Which manifests itselfas symptoms of sloWness of movement (bradykinesia), rigidity, tremor and poor balance in the patient.
Biochemically, dopamine (3,4-dihydroxyphenethylamine) is formed bydecarboxylation of the precursor levodopa (L-dopa; L-3,4-dihydroxyphenylalanine)through the enzyme aromatic L-amino acid decarboxylase (also known as DOPAdecarboxylase (DDC)), both in the brain and in the peripheral circulation. Levodopais in turn produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase (TH).
Dopamine is metabolized to homovanillic acid (HVA) mainly through tWo metabolicpathWays, namely (i) via 3,4-dihydroXyphenylacetic acid (DOPAC) by the enzymesmonoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), and (ii) via 3-methoxytyramine by the enzymes catechol-O-methyltransferase (COMT) and monoamino oxidase (MAO).
The most common treatment of PD aims at restoring the dopamine concentration inthe brain. Administration of dopamine is ineffective because it does not cross the blood-brain barrier. HoWever, since the precursor levodopa does cross the blood- 2 brain barrier, and is converted to dopamine in the brain, administration of levodopa has for a long time been, and still is, the drug of first choice for PD treatment.
Levodopa has a short half-life in the body, 30 to 60 minutes, and upon intake oflevodopa alone, more than 90% is metabolized to dopamine before levodopa reachesthe brain. This makes it necessary to administer large doses of levodopa leading tohigh extracerebral concentrations of dopamine that may often be accompanied bynausea and other adverse side-effects. To increase the bioavailability of levodopa,and reduce its side-effects, levodopa is therefore usually administered concurrentlyWith a decarboxylase inhibitor, typically carbidopa (L-2-hydrazino-3-(3,4-dihydroXyphenyl)-2-methylpropanoic acid), Which inhibits the conversion oflevodopa to dopamine outside the brain, and Which does not cross the blood-brain barrier.
In patients With PD, levodopa may after peripheral administration also be directlymetabolized by the enzyme catechol-O-methyltransferase (COMT) to 3-0-methyldopa (3-OMD; 3-methoXy-4-hydroxy-L-phenylalanine). In order to furtherincrease the levodopa half-life in the body, a catechol-O-methyltransferaseinhibitor, typically entacapone ((2E)-2-cyano-3-(3,4-dihydroXy-5-nitrophenyl)-N,N-diethyl-prop-2-enamide), has been administered in conjunction With levodopa andcarbidopa. Entacapone as a catechol-O-methyltransferase (COMT) inhibitor isdescribed in the European patent No. 0444899 Bl. Another COMT inhibitor usedas an adjunct to levodopa/carbidopa medication is tolcapone (3-dihydroxy-4'- methyl-5-nitrobenzophenone).
Various oral formulations together With inhibitors of enzymes associated With themetabolic degradation of levodopa are Well known, including, for example, Sinemet®and Sinemet®CR sustained-release tablets containing levodopa and carbidopa, and Stalevo® tablets containing levodopa, carbidopa and entacapone.
Oral pharmaceutical compositions including the Stalevo® tablets are disclosed in,for example, US Patent Nos. 6,500,867 Bl and 6,797,732 B2. Alternative oralpharmaceutical compositions comprising levodopa, carbidopa and entacapone aredisclosed in WO 2008/053297, WO 2012/147099, US 2006/0222703, and WO2009/098661.
Before individuals develop clinical symptoms of PD, they Will already have lost 50 to60% of the dopamine neurons in the brain, resulting in a corresponding reductionof approximately 70 to 80% in dopamine concentration. In early disease, survivingneurons are still able to take up levodopa, store it as dopamine, and sloWly releaseit over time in a continuous and relatively constant fashion despite fluctuatingplasma levodopa levels due to the short half life of levodopa and the frequentlyunpredictable intestinal absorption of the oral medicament. With progressive disease, hoWever, more dopamine neurons die and this buffering capacity is lost.
With time patients therefore begin to notice that the beneficial effects of levodopalast a feW hours and then diminish or Wear off, a phenomenon known as motorfluctuations. As more dopamine neurons are lost, a patient's clinical response Willmore closely mirror fluctuations in blood levodopa concentrations, and eventuallythe levodopa response may last only 1 or 2 hours to then Wear off. Due to the lossof the buffering capacity, the dopamine receptors Will be exposed to fluctuatingdopamine concentrations resulting from fluctuating plasma levodopa levels. Whenthe levodopa-derived dopamine concentration in the brain is too high, the patientexperiences dyskinesias (turning movements), and When the brain dopamineconcentration is too loW, PD symptoms return. This creates a therapeutic Windowthat progressively narroWs over time. Once a patient exhibits dyskinesias, theaddition of more dopamine medication Will increase dyskinesias, Whereas areduction in dopamine medication Will increase the off time, Where PD symptoms return.
The pulsatile dopamine stimulation obtained With oral levodopa formulations are only someWhat reduced With sustained release oral levodopa formulations.
For such late stage patients continuous levodopa administration through infusionvia an external pump and directly into the part of the small intestine (duodenum orjejunum) Where most of the levodopa is absorbed has therefore been attempted tothereby provide more continuous plasma levels resulting in reduction in both offperiods and dyskinesias. HoWever, due to the loW aqueous solubility of levodopaand carbidopa, large volumes of levodopa/ carbidopa solutions had to be used Which Were cumbersome and impractical to the patient.
This Was changed With the development of a levodopa/ carbidopa intestinal gelWherein micronized levodopa and carbidopa are suspended in a methyl cellulosethickener gel. An intestinal gel containing 20 mg/ ml levodopa and 5 mg/ mlcarbidopa for intraduodenal infusion is marketed under the trade name Duodopa®.Such pharmaceutical formulations for intraduodenal administration are disclosedin US 5,635,213 and EP 0670713 Bl. Long term 24 hours intestinal administrationof levodopa/ carbidopa is disclosed in WO 2007/ 138086 A1.
Sometimes intraduodenal administration of Duodopa® is combined With oral administration of entacapone.
A stable liquid composition that comprises levodopa, carbidopa and entacaponetogether With arginine and optionally meglumine for inter alia intraduodenal administration is disclosed in WO 2012 /0666538.
A liquid composition of levodopa and carbidopa Which is stabilized by citric acid and EDTA is described in EP 1670450 Bl.
There is a need of pharmaceutical levodopa compositions Which reduce the intake of levodopa With maintained therapeutical effect.
It is an object of the present invention to provide such an improved pharmaceutical composition for intestinal administration of levodopa.
Another object of the present invention is to provide a pharmaceutical composition for intestinal administration of levodopa Which has improved storage stability.
Yet another object of the present invention is to provide an improved method of treating Parkinson's disease, especially in late stages of the disease.
Summary of the invention The above-mentioned objects and advantages are obtained by the present invention as described beloW.
The present invention is based on the finding that in the treatment of Parkinson'sDisease (PD) by administering a combination of levodopa, carbidopa andentacapone, several advantages Will be obtained if all three active substances are provided in a pharmaceutical gel composition for intestinal administration.
Intestinal administration typically is duodenal and/ or jejunal administration via an external access point.
In a first aspect, the present invention thus provides a pharmaceutical gelcomposition for intestinal administration, comprising at least 10 mg / ml of levodopaand at least 2.5 mg / ml of carbidopa, Wherein the gel composition further comprises at least 10 mg / ml of a COMT inhibitor Wherein the COMT inhibitor is entacapone.
In one embodiment, the pharmaceutical gel composition comprises at most 200mg/ml of levodopa, at most 50 mg/ml of carbidopa, and at most 200 mg/ml of a COMT inhibitor, such as entacapone or tolcapone.
In one embodiment, the pharmaceutical gel composition comprises about 20 mg/ ml of levodopa, 5 mg/ ml of carbidopa, and 20 mg/ ml of entacapone.
The pharmaceutical gel composition is advantageously stabilized to reduce thedegradation of especially carbidopa and entacapone on storage, thereby providing a stability of at least 15 Weeks in refrigerated condition, preferably at least 20 Weeks.
In one embodiment, such stabilization is provided by a loWered pH value, typicallynot higher than 5.7, preferably in the range of 4.5 to 5.7, more preferably in therange of pH 4.5 to 5.5, for example about 5.
In another embodiment, stabilization of the gel composition is provided by deoxygenation thereof, typically by nitrogen purging.
In one embodiment, stabilization of the gel composition is provided by the presence of one or more antioxidants, such as ascorbic acid or citric acid. 6 In one embodiment, deoxygenation is combined With loWered pH or antioxidant.
In one embodiment, the gel composition is free from metal chelating agent, such as EDTA.
In one embodiment, the pharmaceutical gel composition is provided in a light- protected container.
In one embodiment, the active substances levodopa, carbidopa and entacapone arein the form of particles having a maximum particle size not exceeding 80 pm andsuspended in an aqueous carrier, Wherein the carrier has a viscosity of at least 300 mPas, measured at a moderate shear rate.
The term moderate shear rate as used herein refers to the shear rate When theaqueous carrier is moderately agitated, corresponding to a shear rate of less thanapproximately 500 s-l but higher than approximately 20 s-l Where the carrier is almost at rest.
In one embodiment, the viscosity of the intestinal gel composition is at least 1800 mPas. In another embodiment, the viscosity is in the range of 2200 to 4500 mPas.
While the carrier typically may be of polysaccharide type, and, for example, beselected from cellulose, methyl cellulose (MC), ethyl cellulose, carboxymethylcellulose (CMC) and salts thereof, xanthan gum, carrageenan, and combinationsthereof the carrier may also be a synthetic polymer, such as polyvinylpyrrolidone(PVP; Povidon) or polyacrylic acid (PAA; Carbomer). An exemplary carrier is thesodium salt of carboxymethyl cellulose (NaCMC).
In one embodiment, the pharmaceutical gel composition comprises 2 % (W / W)micronized levodopa, 0.5 % (W / W) micronized carbidopa, 2 % (W/W) micronized entacapone, and 2.92 % (W / W) sodium carboxymethyl cellulose.
In one embodiment, the pH value of the pharmaceutical gel composition is selected to be the loWest pH value equal to or greater than 5.0 to 5.5 Where the viscosity of 7 the aqueous carrier after 12 days at 25 °C is at least 300 mPas at a moderate shear rate.
In one embodiment, the carrier of the pharmaceutical gel composition is NaCMC, and the pH value is 5.5 i 0.2.
A second aspect of the present invention provides a pharmaceutical gel composition for the treatment of Parkinson's Disease.
In a third aspect of the present invention, there is provided a method of treatingParkinson's Disease, Which comprises intestinally administering a pharmaceutical gel composition according to the first invention aspect as described above.
In one method embodiment, the pharmaceutical gel composition is administered continuously over a period less than 16 hours per day.
In another method embodiment, the pharmaceutical gel composition is administered continuously over a period greater than 16 hours per day.
In yet another embodiment, the pharmaceutical gel composition is administered continuously as a long-term treatment for more than 1 day.
Other embodiments are set forth in the dependent claims.
A more complete understanding of the invention, as Well as further features andadvantages thereof, Will be obtained by reference to the folloWing detailed description read in conjunction With the accompanying draWings.
Brief description of the drawings Figure 1 is a graph shoWing the level of the carbidopa degradation product DHPAversus pH at the end of a 10 days stability test at 25 °C.
Figure 2 is a graph shoWing the level of the carbidopa degradation product DHPPAversus pH at the end of a 10 days stability test at 25 °C.
Figure 3 is a graph showing the level of the entacapone degradation product RRT1 1.8 versus pH at the end of a 10 days stability test.
Figure 4 is a graph showing the level of reduced viscosity versus pH at the end of a 12 days stability test.
Detailed description of the invention The following description is for illustration and exemplification of the invention only and is not intended to limit the invention to the specific embodiments described.
Unless defined otherwise, technical and scientific terms have the same meaning ascommonly understood by one of ordinary skill in the art to which this invention belongs.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.
As mentioned above, the present invention relates to a novel pharmaceuticalcomposition for treating Parkinson's Disease, in the following frequently referred toas PD, by intestinal (typically duodenal or jejunal) administration of levodopa,carbidopa and a COMT inhibitor, typically entacapone, wherein the pharmaceutical composition is characterized by being in gel form.
The term “gel form” as used herein means a semi-solid composition wherein theactive ingredients (levodopa, carbidopa and entacapone) are in the form of particlessuspended in an aqueous carrier having a viscosity of at least 300 mPas, at a moderate shear rate, as defined above.
The novel composition of the invention differs from the previously knownlevodopa/ carbidopa intestinal gel (in the following for brevity “LCIG”), sold underthe trade name Duodopa®, in that the present composition additionally contains entacapone. 9 In comparison With LCIG, the inclusion of entacapone in the intestinal gelcomposition Will reduce the daily levodopa intake, typically by 10-30%, therebyreducing the risk of the patient developing levodopa-related side effects, such as dyskinesia and motor fluctuation.
Reduction of the levodopa intake is also highly desirable due to the fact that moresevere neurographic abnormalities have been reported in patients treated With LCIGinfusion than in orally treated patients, the degree of the severity of the neuropathic change correlating With increased dose of levodopa.
It also goes Without saying that administration of entacapone via the intestinal gelcomposition rather than by separate oral administration of entacapone combinedWith LCIG administration Will ensure a more even and controlled entacapone delivery.
In the intestinal gel composition, the particles of the active ingredients typicallyhave a maximum particle size not exceeding about 80 pm. The particles mayadvantageously be micronized. Further, the aqueous carrier has a viscosity of atleast 300 mPas, usually in the range of 300 to 5000 Pas, at a moderate shear rate (between 20 and 500 s-l).
The carrier is preferably of plastic or pseudoplastic nature so that the viscosity Will be loWered during agitation, Whereby the liquid aqueous carrier Will be easier to plllTlp.
The aqueous carrier is usually a dispersion or solution of a pharmaceuticallyacceptable colloid, typically a Water-soluble or Water-sWellable colloid ofpolysaccharide type, including, for instance cellulose, methyl cellulose, ethylcellulose, carboxymethyl cellulose and salts thereof, xanthan gum, carrageenan, ora synthetic polymer, e.g. polyvinylpyrrolidone or polyacrylic acid, combinations thereof.
The viscosity of the gel composition should be sufficiently high to carry the drug load of active ingredients Without a tendency of sedimentation. At the same time the viscosity should not be too high so that it should be possible to pump the gel, preferably With an ambulatory pump (With reasonable battery consumption).
A suitable viscosity may be obtained by adjusting the molecular Weight of thecolloid used into a suitable range, such as by adjusting the degree ofpolymerization. The viscosity may furthermore be adjusted by selecting a suitable concentration of the colloid in the aqueous system.
Usually, the viscosity of the intestinal gel composition is at least 1800 mPas, and is typically in the range of 2200 to 4500 mPas.
The intestinal gel composition may be prepared by mixing the carrier With Water toform a gel and then dispersing finely the active components (levodopa, carbidopaand entacapone) in the aqueous carrier using methods and apparatus Which areWell-known to those skilled in the art. The prepared formulations are then dispensed into suitable containers for intestinal, such as duodenal, administration.
The intestinal gel composition is administered via intestinal administration,preferably directly into the intestine, e.g. duodenum or jejunum, by a direct jejunostomy, or via a percutaneous endoscopic gastrostomy.
In an advantageous embodiment, the gel is administered With a portable pump, typically of peristaltic or syringe type. An exemplary peristaltic pump is that sold under the trade name CADD-Legacy Duodopa® pump (Smiths Medical, MN, U.S.A.).
In this case the gel is contained in a cassette, pouch or vial that is attached to thepump to create the delivery system. The delivery system is then connected to theduodenal tube or the jejunum tube for intestinal administration. An example of asyringe type delivery system is the portable pump sold under the trade name Cane Crono Infusion Pump (Applied Medical Technology Ltd., Cambridge, U.K.).
While for treating PD the intestinal gel of the invention typically is administeredcontinuously over a period of up to 16 hours per day, the gel may also beadministered over a period of greater than 16 hours per day, such as up to 24 hours per day, or continuously for more than one day. 11 An important aspect of the present invention relates to the storage stability, or shelf life, of the intestinal gel.
The shelf life of the prior art intestinal gel LCIG in refrigerated condition is basicallydetermined by the degradation of carbidopa, and more specifically the level of the degradation product hydrazine Which is considered to be genotoxic.
While levodopa has been found to be relatively stable in the prior art LCIG as Wellas in the intestinal gel composition of the invention, carbidopa has been found todegrade about 50 percent quicker in a corresponding intestinal gel composition Which additionally contains entacapone.
An increase of the stability of the levodopa/ carbidopa/entacapone composition ofthe invention to have, for instance, a stability of 15 Weeks, preferably 20 Weeks in arefrigerated condition, When the active ingredients should still have a meaningfultherapeutic effect, may be accomplished by different means, separately, or, optionally, by tWo or more of them in combination.
According to the invention, the stability of the intestinal gel composition may beincreased by adjusting the pH of the gel composition to not be higher than about5.7 (i.e. equal to or loWer than 5.7).
Generally, the stability of the active substances (primarily carbidopa) in the gelcomposition increases as the pH is loWered. On the other hand, hoWever, thestability of the gel per se decreases With loWer pH (being destabilized by breakingdoWn of the viscosity). Further, too loW a pH value of the gel composition is detrimental to the patient's intestine.
According to the invention, it has been found that increased storage stability Withregard to the active substances as Well as to the gel structure and to the sensitivityof the patient's intestine is achieved by careful selection of the pH to be Within anoptimum range of from about 4.5 to about 5.7, preferably 4.5 to 5.5, for exampleabout 5.0. 12 Acidic adjustment of the pH may be effected by a mineral acid, such as hydrochloric acid, or an organic acid, for example citric acid or citric buffer.
Alternatively, or in addition to pH stabilization, stabilization of the gel compositionmay be effected by oxygen removal Which may be done by Well known methods,typically by purging With nitrogen gas.
Yet an alternative Way of stabilizing the intestinal gel composition is to introduceone or more antioxidants, such as e.g. ascorbic acid or citric acid, into the gel.Other antioxidants that may be used may readily be selected by a person skilled in the art from commonly known antioxidants.
Storage of the gel composition in a light reducing container, such as an aluminiumbag, has also been found to have some positive effect on the degradation of carbidopa and entacapone.
In an advantageous embodiment, the intestinal gel composition of the invention hasa pH of about 5, is deoxygenized With nitrogen gas, and is preferably provided in a light protected container.
Heavy metals are known to catalyse the degradation of carbidopa. While prior artlevodopa/ carbidopa formulations have been shoWn to be stabilized by EDTA, Whichhas a great chelating property, the stability of the intestinal gel composition of theinvention has surprisingly been found to be negatively affected by EDTA. The gel composition of the invention is therefore preferably free of any chelating agent.
In the folloWing, non-limiting embodiments of the intestinal gel composition of the present invention and comparative experiments thereWith Will be described.
EXPERIMENTAL PART In the folloWing, experiments Will be described performed With an embodiment ofintestinal gel composition according to the present invention, beloW referred to as“TRIGEL”, and With the prior art commercial levodopa/ carbidopa intestinal gel,Duodopa®, beloW referred to as “LCIG”, as Well as With modified TRIGEL 13 compositions for stability tests. The compositions of LCIG and TRIGEL are given inTables 1 and 2 below.
Table 1 - Composítíon of LCIG Substance Amount Micronized levodopa 2 % (W / W) (20 mg/ ml)0.5 % (W/W) (5.0 mg/ml)2.92 % (W/W) 94.58 % (W/W) Micronized carbidopaNaCMC Purified Water Levodopa, an aromatic amino acid, is a White, crystalline compound, slightlysoluble in Water, With a molecular Weight of 197.2. It is designated chemically as (-)-L-d-amino-ß-(3,4-dihydroXybenzene) propanoic acid. Its empirical formula is C9H11NO4 and its structural formula is: Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a White,crystalline compound, slightly soluble in Water, With a molecular Weight of 244.2. Itis designated chemically as (-)-L-d-hydrazino-d-methyl-ß-(3,4-dihydroxybenzene)propanoic acid monohydrate. The gel content is expressed in terms of carbidopamonohydrate, Which has a molecular Weight of 226.3. Its empirical formula is C10H14N2O4X H20, and its structural formula is: 14 NaCMC is the sodium salt of carboxymethyl cellulose, a polymer derived from natural cellulose Which is highly Water-soluble.
Table 2 - Composítíon of TRIGEL Substance Amount Micronized levodopa 2 % (W / W) (20 mg/ ml)0.5 % (W/W) (5.0 mg/ml)2 % (W/W) (20 mg/ml)2.92 % (W/W) 92.58 % (w/w) Micronized carbidopaMicronized entacaponeNaCMC Purified Water Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is a nitro-catechol-structured compound With a molecular Weight of 305.3. The chemicalname of entacapone is (E)-2-cyano-3-(3,4-dihydroXy-5-nitrophenyl)-N,N-diethyl-2- propenamide. Its empirical formula is C14H15N3O5.
Manufacture of test samples 15 small scale batches as described in Table 3 Were manufactured as describedbeloW and filled into syringes for initial and stability evaluation in various storageand use conditions. The batch size of the experiments Was 100 to 500 g. In Table 3,API is active pharmaceutical ingredient, L is levodopa, C is carbidopa, and E is entacapone.
Table 3 Exp. API (mg/ g) pH Formulation 1 L:20, C:5 6.1 Reference 2 L:20, C:5, E:20 5.7 Reference + Entacapone 3 L:20, C:5, E:20 5.6 0.05% EDTA 4 L:20, C:5, E:20 5.60 0.5 % citric acid (NaOH for pH adjustment) 5 L:20, C:5, E:20 5.75 0.1 % ascorbic acid (NaOH for pH adjustment)6 L:20, C:5, E:20 5.03 LoW pH (target pH 5.0) 7 L:20, C:5, E:20 7.0 High pH (target pH 7.0) 8 L:20, C:5, E:20 5.7 Aluminium bag (composition 2) 9 L:20, C:5 - Reference With 0.5 % citric acid + 0.05% EDTA10 L:20, C:5, E:20 5.6 0.5 % citric acid + 0.05% EDTA 1 1 L:20, C:5, E:20 5.86 Reference Trigel 12 L:20, C:5, E:20 5.5 0.5% citrate buffer (citric acid/ sodium citrate)13 L:20, C:5, E:20 5.0 0.5% citrate buffer (low pH) 14 L:20, C:5, E:20 5.75 0.1 % ascorbic Acid + 0.05% EDTA 15 L:20, C:5, E:20 5.86 Deoxydation using Ng Manufacturing process The general manufacturing process of the samples to be tested is described beloW. 1) Sodium carboxymethylcellulose Was added to purified Water in a Pyrex beaker during homogenization for 1-2 minutes until a lump free viscous solution Was achieved. 2) The active ingredients levodopa, carbidopa and entacapone Were added and homogenized until a homogenous suspension Was achieved. 3) Additional excipients as described in Table 3 above Were added during homogenization until dissolved. 4) If needed, the pH Was adjusted to the target by addition of sodium hydroxide or hydrochloric acid solution during mixing. 5) Manual filling of the suspension into syringes. 16 The process equipment used for manufacturing of the experimental batchesincluded a Silverson L5M Homogenizer (Silverson Machines Ltd., Chesham, U.K.),and a IKA Janke 85 Kunkel RWQSW Mixer (IKA Works GmbH, Staufen, Germany).
The following analytical equipment Was used for physical analysis and in processcontrols during the manufacturing: pH-meter - Mettler Toledo Seven CompactTM With Inlab Micro electrode (Mettler-Toledo Inc., Columbia, OH, U.S.A.).
Viscometer - Brookfield DV-ITM Prime With small sample adapter (BrookfieldEngineering, Middleborough, MA, U.S.A.).
HPLC - Agilent 1 100 With DAD detector and cooled injector; OpenLAB CDSChemstation C.O1.05 (Agilent Technologies Inc., Santa Clara, CA, U.S.A.).
Stability experiments1. Stability of unstabilized TRIGEL vs LCIG The stability of unstabilized TRIGEL Was compared With that of LCIG With regard tothe stability of carbidopa, especially its degradation product hydrazine Which isconsidered to be genotoxic. Hydrazine is formed in equal molar number as 3,=1E---diflclyfaíïrawxyjçzlcleriylacetone (DHPA), Which is easier to measure and Was therefore usedas reference in this as Well as in the other experiments beloW. The results are shoWn in Table 4 beloW. 17 Table 4DHPA (area % of. b°dExp' Formulatzon 5 dayïazçt I :åugays at25°C 25°C1 LCIG: 20/5 mg/ml Q 3.08 5-1levodopa/ carb1dopa suspensionTRIGEL: 20/5/20 mg/ml2 levodopa/ carbidopa/ entacapone 4.76 7.65suspensionComparing 1 With 2 +55% +50% As shown in Table 4, carbidopa degrades about 50% quicker in the triple levodopa-carbidopa-entacapone gel suspension (TRIGEL) compared to a corresponding levodopa-carbidopa gel suspension (LCIG). 2. Stabilization of TRIGEL Stabilization experiments With TRIGEL With regard to carbidopa, levodopa andentacapone Were performed in an accelerated stability study at 25 °C for 12 days.As reference product, TRIGEL having no stabilizing modification Was used. Inaddition to determination of DHPA, an additional carbidopa degradation product,3,4-dihydroxyphenylpropionic acid (DHPPA), as Well as an (so far) unidentified degradation product of entacapone Were measured.
The folloWing stabilizing modifications of the TRIGEL composition Were tested, thecorresponding experimental compositions (“Exp.”) in Table 3 above being givenWithin parentheses:1. Varied pH (Exp. 6, 7)2. Addition of anti-oxidant a) O.1% ascorbic acid (Exp. 5) b) O.5% citrate buffer (Exp. 12) c) O.5% citric acid (Exp. 4)3. Removal of oxygen nitrogen gas (Exp. 15)4. Removal of metal ions 0.05% EDTA (Exp. 3) 18 5. Combination of reduced pH and anti-oxidant (Exp. 13) 6. Combination of anti-oxidant and removal of oxygena) O. 1% ascorbic acid and 0.05% EDTA (Exp. 14)b) O.5% citric acid and 0.05% EDTA (Exp. 10) 7. Enclosure in an aluminium bag (Exp. 8).
The results are presented in Table 5 beloW. The results are ranked With respect toreduction of hydrazine (DHPA, RRT 7.1). RRT 8.5 is DHPPA, and RRT 1 1.8 is adegradation product of entacapone. Levodopa Was stable in all combinations and istherefore not included in the table. In the table, “Carb” is carbidopa, and “Ent” is entacapone. 19 Table 5D d t'Formulatíon prfiåïztgßtår;TRIGEL = 20/5/20 Carbido a EntExp. mg/ ml of levodopal P ° Commentcarbidopa/ DRHÉ: RRT RRTentacapone 7 1 3,5 11,36 pHipH âïiïëifgloiitaïiïfgatäfion50) -73% -77% -76% both Carb and Ent ^::::::i::1:iï:::i;ïaf5 aswfbíc acid (NaOH :tabiiit ofåoth carb andfor pH-adjustment) 42% _1O% _25% Ent yDeoxygenized suspension15 TRIGEL deoxygenized With Ng has a clear positiveWith Ng impact on both Carb and-37% -12% -42% EntTRIGEL + O.5% citrate Citrate buffer has a positive12 buffer (citric impact on both, more soacid / sodium citrate) 1% -13% -23% om EntTRIGEL + 0.5 % citric Citrate acid has a slight4 acid (NaOH for pH- positive impact on bothadjustment) 2% -17% -9% Carb and EntEDTA has a negative3 TRIGEL + 0.05% EDTA impact on the stability of20% 32% 38% both Carb and EntTRIGEL + High pH (pH Increased pH has' the7 7 O) clearest negative impact on' 109% 713% 703% both Carb and EntCitrate buffer in aIclombination Wišlp a loWtpHh. as a positive e ect on ot13 4I:I%)5% Cltrate Carb and Ent. HoWever thep combination does not offerany benefits compared to-9% -78% -74% only reducing pH.Ascorbic acid in :zïïlnïïiïazïïëåïïfint14 ascorbic Acid + 0.05% p .EDTA anddone IdegraCdatLonro uct orm ar ,10% -49% -45% however negative on DHPA.TRIGEL + Aluminium Aluminium bag has minor impact8 . on both Carb and Ent, likely duebag (formulatlon 2) -2% -8% to reduced light exposure.TRIGEL + 05 % citric A combination of both .citric acid10 acid + O 050/ EDTA and EDTA has a negative impact' 0 29% 85% on both carbidopa and entacapone 3. pH ímpactíng effect on the stability of TRIGEL As shown in Table 5 above, pH has the greatest impact on the stability of bothcarbidopa and entacapone, its impact, however, being reduced With a reduced pH.The level of degradation products formed at the end of an accelerated stabilitystudy, 10 days at 25 °C, at different pH of the gel suspension are shoWn in Figure 1(Carbidopa: DHPA), Figure 2 (Carbidopa: RRT 8.5 = DHPPA), and Figure 3 (RRT 1 1.8). 4. Víscosíty While, as demonstrated above, a loWer pH has a positive impact on the stability ofboth carbidopa and entacapone, hoWever, a loWer pH breaks doWn the viscosity ofthe NaCMC gel. Figure 4 shoWs the level of reduced viscosity at end of an accelerated stability study, 12 days at 25 °C, at different pH of the gel suspension. 5. Stabílíty of TRIGEL, summary According to the test results obtained, the final formulation should have a reducedpH. A reduced pH, hoWever, has tWo main draWbacks. Firstly, it breaks doWn theviscosity Which destabilizes the suspension (sedimentation), the loWer the pH is thequicker the gel breaks doWn, and secondly, a loW pH may cause an irritation of theintestine at the site of administration. A viscosity reduction of maximum 1000 cP after 12 days Would be acceptable Which corresponds to a pH of about 4.9 - 5.0.
A pH of about 5 Will likely not cause any irritation at the site of administrationconsidering, among other things, the loW daily volume of TRIGEL administered (100ml) compared to the about 10 liter of gastric juice passing the intestine per day, the gastric juice in addition being buffered.
Therefore, a suspension having a pH of about 5, stabilized With citric acid,deoxygenized With Ng, and having a container With light protection Will likely givethe best possible stability. A suitable alternative is a suspension having a pH ofabout 5, stabilized With ascorbic acid, deoxygenized With Ng, and having a container With light protection. 21 Heavy metals are known to catalyse the degradation of carbidopa. It is Well knownthat EDTA has a great chelating property and that EDTA has shoWn stabilizingeffects on carbidopa in a levodopa - carbidopa formulation. It Was thereforesurprising that EDTA had a negative impact on the stability of the present intestinal gel formulation.
The present invention is not limited to the above-described preferred embodiments.Various alternatives, modifications and equivalents may be used. Therefore, theabove embodiments should not be taken as limiting the scope of the invention, Which is defined by the appending claims.

Claims (13)

Claims
1. A pharmaceutical gel composition for intestinal administration,comprising at least 10 mg/ ml of levodopa and at least 2.5 mg/ ml of carbidopa,Wherein the gel composition further comprises at least 10 mg/ ml of a COMT inhibitor Wherein the COMT inhibitor is entacapone.
2. The pharmaceutical gel composition according claim 1, Wherein the gelcomposition has a pH value equal to or lower than 5.7, preferably in the range of from 4.5 to 5.5.
3. The pharmaceutical gel composition according to any one of claims 1 or 2, Wherein the gel composition is deoxygenized.
4. The pharmaceutical gel composition according any one of claims 1 to 3, Which further comprises an antioXidant.
5. The pharmaceutical gel composition according claim 4, Wherein the antioxidant is ascorbic acid or citric acid.
6. The pharmaceutical gel composition according to any one of claims 1 to 5, Wherein the gel composition is free from metal chelating agent.
7. The pharmaceutical gel composition according to any one of claims 1 to 6, Wherein the gel composition is provided in a light-protected container.
8. The pharmaceutical gel composition according to any one of claims 1 to7, Wherein levodopa, carbidopa and entacapone are in the form of particlessuspended in an aqueous carrier, the particles having a maximum particle size notexceeding 80 um, Wherein the carrier has a viscosity of at least 300 mPas at a moderate shear rate.
9. The pharmaceutical gel composition according to claim 8, Wherein thecarrier is of polysaccharide type, preferably selected from cellulose, methylcellulose, ethyl cellulose, carboxymethyl cellulose and salts thereof, and combinations thereof.
10. The pharmaceutical gel composition according to claim 9, Wherein the carrier is sodium carboxymethyl cellulose.
11. 1 1. The pharmaceutical gel composition according to any one of claims 1 to10, Wherein the gel composition comprises 2 % (W/W) micronized levodopa, 0.5 %(W/W) micronized carbidopa, 2 % (W/W) micronized entacapone, and 2.92 % (W/W) sodium carboxymethyl cellulose.
12. The pharmaceutical gel composition according to any one of claims 9 to1 1, Wherein the pH value of the gel composition is selected to be the loWest pHvalue equal to or greater than 5.0 to 5.5 Where the viscosity of the aqueous carrier after 12 days at 25 °C is at least 300 mPas at a moderate shear rate.
13. A pharmaceutical gel composition according to any one of claims 1 to 12 for the treatment of Parkinson's Disease.
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SE1451034A SE538425C2 (en) 2014-09-04 2014-09-04 Pharmaceutical compositions comprising levodopa, carbidopa and a comt inhibitor and method of administration thereof
PL15838800T PL3188725T3 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
DK15838800.9T DK3188725T3 (en) 2014-09-04 2015-09-04 PHARMACEUTICAL COMPOSITIONS INCLUDING LEVODOPA, A DOPAMINE DECARBOXYLASE INHIBITOR AND A COMT INHIBITOR AND METHOD OF ADMINISTRATION
ES20200070T ES2973289T3 (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapone
SI201531992T SI3782617T1 (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapone
US15/507,959 US10071069B2 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof
PT158388009T PT3188725T (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
JP2017533154A JP6622310B2 (en) 2014-09-04 2015-09-04 Pharmaceutical composition comprising levodopa, dopamine decarboxylase inhibitor and COMT inhibitor and method of administration thereof
AU2015312430A AU2015312430B2 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof
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PT202000709T PT3782617T (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapon
EP23219005.8A EP4356907A1 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comtinhibitor and method of administration thereof
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CN201580050984.7A CN107072973A (en) 2014-09-04 2015-09-04 Pharmaceutical composition and its application process containing levodopa, dopamine decarboxylase enzyme inhibitor and COMT inhibitor
PCT/SE2015/050939 WO2016036308A1 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
HRP20240314TT HRP20240314T1 (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapon
EP15838800.9A EP3188725B1 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
FIEP20200070.9T FI3782617T3 (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapone
DK20200070.9T DK3782617T3 (en) 2014-09-04 2015-09-04 PHARMACEUTICAL GEL COMPOSITIONS COMPRISING LEVODOPA, CARBIDOPA AND ENTACAPONE
EP20200070.9A EP3782617B1 (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapone
CA2959307A CA2959307C (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
ES15838800T ES2844500T3 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor, and method of administration thereof
SI201531474T SI3188725T1 (en) 2014-09-04 2015-09-04 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
RS20240276A RS65337B1 (en) 2014-09-04 2015-09-04 Pharmaceutical gel compositions comprising levodopa, carbidopa and entacapone
US16/054,392 US10786472B2 (en) 2014-09-04 2018-08-03 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof
JP2019210309A JP6889231B2 (en) 2014-09-04 2019-11-21 A pharmaceutical composition containing levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor, and a method for administering the same.
US16/992,824 US11413262B2 (en) 2014-09-04 2020-08-13 Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof
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