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WO1997016181A1 - Administration par voie intranasale de bioprecurseurs du levodopa - Google Patents

Administration par voie intranasale de bioprecurseurs du levodopa Download PDF

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Publication number
WO1997016181A1
WO1997016181A1 PCT/US1996/017740 US9617740W WO9716181A1 WO 1997016181 A1 WO1997016181 A1 WO 1997016181A1 US 9617740 W US9617740 W US 9617740W WO 9716181 A1 WO9716181 A1 WO 9716181A1
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Prior art keywords
dopa
administration
ester
nasal
dopamine
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PCT/US1996/017740
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English (en)
Inventor
Anwar A. Hussain
Soichi Itoh
Lewis Dittert
Huaihung Danny Kao
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University Of Kentucky
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Application filed by University Of Kentucky filed Critical University Of Kentucky
Priority to AU76694/96A priority Critical patent/AU7669496A/en
Publication of WO1997016181A1 publication Critical patent/WO1997016181A1/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • L-dopa to the brain of a mammal in need of treatment with this drug, by administering water-soluble prodrugs of L-dopa intranasally. More specifically, this invention relates to the enhancement of L-dopa treatment by intranasal administration of water-soluble esters of L-dopa. The invention is particularly useful in the treatment of Parkinson's disease.
  • Parkinsonism is a clinical syndrome composed of four features: bradykinesia, muscular rigidity, resting tremor, and abnormalities of posture and gait. This disorder results from damage to the basal ganglia of the brain, particularly the substantia nigra.
  • nervous signals pass from the brain's cortex through the reticular formation and spinal cord to muscles.
  • a negative-feedback signal passes to the basal ganglia via a second pathway, producing a damping effect on the corticospinal pathway. This feedback signal reduces muscle tone, resulting in smooth, jerk- free muscle control during movement.
  • Dopamine a neural transmitter produced by the substantial nigra, is primarily responsible for producing this damping effect.
  • Another transmitter, acetylcholine inhibits the damping effect.
  • a balance is maintained between dopamine and acetylcholine in the healthy state.
  • Parkinson's disease as the result of degeneration of the basal ganglia, dopamine activity is decreased, while acetylcholine activity remains. As a result, the muscles are over-tense, causing tremor, joint rigidity, and slow movement (bradykinesia).
  • Most drug treatments for Parkinson's are based on either increasing the level of dopamine in the brain or neutralizing the action of acetylcholine.
  • Parkinson's disease usually become manifest after the age of 55, and increase after the age of 65. Left untreated, Parkinsonian patients become rigid and akinetic, and require constant care. Death is usually due to the complications of pulmonary embolism, aspiration, or hypostatic pneumonia. In spite of advanced understanding of its pathophysiology and treatment, the root causes of Parkinsonism remain unknown.
  • Amelioration of dopaminergic transmission restores motor ftinction in Parkinsonism. This amelioration forms the central strategy of almost all current drug regimens for the treatment of this disease.
  • systemic administration of dopamine does not result in higher brain dopamine levels, because dopamine cannot cross the blood-brain barrier.
  • L-dopa its precursor, L-dopa, can cross the blood-brain barrier. Once in the brain, L-dopa is metabolized (decarboxylated) to form dopamine.
  • L-dopa is currently considered the first- line therapy for the management of Parkinson's syndrome 3 .
  • L-dopa is L-3,4-dihydroxyphenylalanine ( Figure 1). It is an odorless white to off-white crystalline powder which melts with decomposition at 270 "C.
  • L-dopa exists in different ionic forms depending on the pH of the solutions. At a range of pH from 3 to 9, L-dopa exists as a zwitterion. This contributes to its low water solubility in this pH range, as shown in Figure 2 10 .
  • L-dopa represents the most clinically useful drug in the treatment of Parkinson's disease, because unlike dopamine, L-dopa crosses the blood-brain barrier and is converted to dopamine in the brain.
  • the magnitude of improvement in Parkinsonism with L-dopa therapy has not been surpassed by any other available anti-Parkinsonian agent 3 .
  • L-dopa is typically administered orally in large doses, either by itself (i.e. , Larodopa ® ) or in combination with a decarboxylase inhibitor (i.e. Sinemet ® ).
  • a decarboxylase inhibitor i.e. Sinemet ®
  • the oral bioavailability of L-dopa administered alone is estimated to be only about 5 to 10%, and only 3 % of the administered oral dose actually reaches the brain.
  • L-dopa undergoes carrier-mediated active transport absorption in the intestine 14 . It has been shown, in studies carried out in isolated dog intestinal segments in situ, that the major absorption site for L-dopa is the duodenum 11 . The extent of absorption decreases after the drug passes the upper part of the small intestine. Figure 3 shows that the duodenal segment of the dog intestine is the most efficient absorption site. Such site-specific absorption limits the extent of absorption of orally administered L-dopa. Second, L-dopa undergoes extensive metabolism in the gastrointestinal
  • GI GI wall during the absorption process.
  • the plasma levels of L- opa alter intravenous and hepatic portal infusions in dogs are identical, whereas the plasma level after duodenal administration is extremely low 16 .
  • Metabolism of L-dopa in the GI wall appears to be dose-dependent.
  • the area under the blood level curve increases disproportionately as a function of the oral dose, possibly due to a saturable metabolic process 11 .
  • the oral bioavailability of L-dopa without decarboxylase inhibitors is 15% at a dose of 3.8 mg/kg/day and 33% at a dose of 15.4 mg/kg/day. At higher doses, the enzymes become saturated, resulting in disproportionately higher bioavailability.
  • L-dopa is metabolized to several products ( Figure 5) 13 , some of which have their own pharmacological activities and side effects.
  • the metabolism of L-dopa occurs mainly by decarboxylation and conjugation in the gastrointestinal tract before entering the systemic circulation.
  • One major pathway for the metabolism of L-dopa is its decarboxylation to dopamine ( Figure 6) 14 .
  • L-dopa the major peripheral side-effects resulting from the oral administration of L-dopa are due to the formation of large amounts of dopamine during first-pass metabolism in the GI wall. These side-effects include nausea, vomiting and cardiac irregularity. Thus, the lowest possible dose of L-dopa which can be administered is desired because of the undesirable systemic side effects.
  • L-dopa Inter- and intraindividual variability in the degree of this first-pass effect is the main cause of the common difficulty of maintaining an effective therapeutic regimen with L-dopa.
  • decarboxylase inhibitors may be coadministered with L-dopa.
  • the most notable effect of this co-administration is a 75% reduction in total daily L-dopa dose required to produce clinical benefit 13 15 .
  • the oral bioavailability of L-dopa is doubled by coadministration of dopa decarboxylase inhibitors 16 , and C ⁇ JJU . (maximum concentration) and AUC (Area Under the Curve) for a given dose are also increased 17 .
  • Intravenous infusion is impractical and inconvenient for routine clinical use because of the large volumes of fluid required and the acidity of L-dopa solutions, let alone the fact that patients would rather not have to inject themselves each day in order to get the desired clinical effect.
  • Attempts to enhance the bioavailability and minimize the side effects of L-dopa administration include modifications in the formulation of L-dopa-containing pharmaceutical compositions, and utilization of prodrugs of L-dopa orally and rectally. While none of these approaches have overcome the difficulties with L-dopa, nevertheless, a brief description of each attempt is discussed below.
  • the bioavailability for oral extended-release Sinemet ® CR4 tablets is about 70-75% of that for standard Sinemet ® tablets. To compensate for the differences, the total dose for patients taking Sinemet ® CR4 tablets is about 25% more than that for the standard Sinemet ® formulation 24,25 . Sinemet ® CR4 (50/200) allowed a slight extension in the interval between doses as compared with standard Sinemet ® .
  • the controlled released Sinemet ® CR4 can reduce but not eliminate fluctuations in response.
  • the application of this technology will continue to be limited by factors such as erratic gastric emptying time.
  • the Sinemet ® CR4 is not an ideal formulation, and there are significant problems associated with its use.
  • the slow rise and fall of plasma L-dopa levels cause successive doses to contribute to progressively higher levels of the drug late in the day, in turn causing prolonged and at times severe dyskinesia.
  • L-dopa Another approach to achieving improved bioavailability of L-dopa is to modify L-dopa structurally 28 and possibly select a route of administration other than the oral route.
  • the transient modification is intended to (a) increase water solubility, (b) increase lipid solubility, and (c) protect the drug from enzymatic inactivation.
  • Most of the chemical modifications involve the esterification of the catechol or the carboxylic acid moieties. The conversion of these prodrugs to the parent compound by widely distributed esterases makes such structural modification very attractive.
  • nasal route of administration has received a great deal of attention as a convenient and reliable method for the administration of drugs, and serves as an alternative to intravenous administration.
  • butorphanol tartrate (Stadol NSTM) is ineffective orally but is commercially available in the form of a nasal spray.
  • the rate and extent of absorption of drugs from the rat nasal cavity matches that in humans.
  • the nasal absorption of propranolol 5 1 - 7 is identical in both rats and human.
  • Figures 10 and 11 show plasma levels for propranolol in rats and humans 6 - 7 .
  • the rat is a good model for studying the nasal absorption of L-dopa and its prodrugs.
  • the present inventors have found that the nasal route of administration of water-soluble prodrug of L-dopa offers significant advantages over the prior art. Those advantages include almost 100% bioavailability, no dopamine in the plasma thereby avoiding undesirable systemic side effects and a much larger dose actually reaching the brain to achieve the desired clinical effect.
  • L-dopa is too insoluble to be used in conventional intranasal formulations, and since water-soluble prodrugs of L-dopa are ineffective when administered orally or rectally, it is an object of the present invention to provide a method for treating dopamine deficiency comprising intranasal administration of water soluble prodrugs of L-dopa. It is a further aspect of this invention to provide a method for administering L-dopa in a manner which significantly enhances plasma levels of L-dopa, and thus its bioavailability, compared to prior art methods.
  • This object has been achieved in the present invention by the nasal administration of water-soluble esters of L-dopa.
  • a further aspect of this invention is to provide a pharmaceutical composition suitable for intranasal administration, for treatment of dopamine deficiency, including Parkinson's disease.
  • the composition of the present invention comprises a water-soluble prodrug of L-dopa and a pharmaceutically acceptable carrier.
  • Figure 1 Chemical structure of L-dopa.
  • Figure 2 pH-solubility profile for L-dopa at 37'C.
  • Figure 3 Average AUC of L-dopa up to 1 hour after administration of single 100 mg dose of L-dopa to dog duodenum, jejunum, and ileum.
  • Figure 4 Average plasma levels of L-dopa following three routes of administration of single 20 mg dose of L-dopa to dogs.
  • Figure 5 Major metabolic pathways of L-dopa.
  • Figure 6 Average ( ⁇ SE) plasma levels of L-dopa (A) and total dopamine (B) following oral administration of L-dopa to three patients. Key: A , 3.8 mg/kg; 0 ,7.7 mg/kg; and # ,15.4 mg/kg
  • FIG. 7 Plasma L-dopa levels (filled symbols and left-hand scales) and clinical performance (open symbols and right-hand scales) in a patient with response fluctuations during administration of standard Sinemet ® tablets (25/100)(A), intermittent duodenal (B), continuous gastric infusion (C), and duodenal infusion (D) of L-dopa; dots at the top of graphs A, and B, denote times of drug administration. • , plasma L-dopa; O , mobility
  • Figure 8 A comparison of in vivo plasma levels of L-dopa following administration of CR3 and CR4 tablets.
  • Figure 9 Parkinson mobility scores (right panel) and plasma L-dopa levels for a typical patient taking standard Sinemet ® (open symbols and dashed lines) every 3 hours, and Sinemet ® CR4 (close symbols) every 6 hours.
  • Figure 10 Time course of the average blood propranolol levels in three rats following nasal administration of 1 mg/rat (O), intravenous administration of 1 mg/rat ( A ), oral administration of 1 mg/rat (•), and nasal administration of 2 g/raL ( )
  • Figure 11 Time course of the average serum propranolol levels in six male subjects following nasal administration of 10 mg/subject ( ⁇ ), intravenous administration of 10 mg/subject (O), and oral administration of 80 mg/subject (D).
  • Figure 12 In-vivo rat nasal operation.
  • Figure 13 Effect of buffer concentrations on the degradation rate constants of L-dopa butyl ester at 37'C.
  • Figure 14 pH-rate profiles for the butyl ester at 37'C.
  • Figure 15 The degradation of the butyl ester in rat plasma.
  • Figure 16 The degradation of the butyl ester in rat brain homogenate.
  • Figure 17 The degradation of the butyl ester in rat CSF (cerebrospinal fluid).
  • Figure 18 The degradation of the butyl ester in the rat nasal perfusate.
  • Figure 20 The nasal absorption profiles of the butyl ester at 4, 20, 40 mg/kg
  • Figure 22 L-dopa and dopamine levels following nasal and intravenous administrations of L-dopa butyl ester at 20 mg/kg L-dopa equivalent dose.
  • Figure 25 Olfactory bulb L-dopa levels following nasal and intravenous administrations of L-dopa butyl ester at 20 mg/kg L-dopa equivalent dose.
  • Figure 27 Experimental and calculated plasma levels for L-dopa in rat plasma.
  • the present inventors have discovered a new and novel method for the treatment of dopamine deficiency, by the intranasal administration of a water- soluble prodrug of L-dopa.
  • This method offers significant clinical advantages over the prior art. More specifically, the inventors sought to provide a safe, effective and convenient treatment for Parkinson's disease which comprises the administration of water-soluble prodrugs of L-dopa intranasally, thus avoiding the side-effects associated with oral dosage forms.
  • a prodrug is a compound formed by chemical modification of a biologically active compound which will liberate the active compound in vivo by enzymatic or hydrolytic cleavage. Advantages of this approach include reduction of general cytotoxicity, better bioavailability of active drug or longer duration of action. Any water soluble prodrug of L-dopa is useful in the practice of this present invention.
  • esters of L-dopa i.e. , prodrugs of L-dopa
  • Intranasal administration of these compounds is as effective as intravenous administration of L-dopa, but may be conveniently and painlessly self-administered by the patient.
  • Preferred L-dopa esters include alkyl, cycloalkyl, and aryl esters, particularly methyl, butyl, pentyl, cyclohexyl, and benzyl esters, and pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts of an acid group or an amino group include, but are not limited to, salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- tolylsulfonic acids, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- tolylsulfonic acids
  • inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • a still further aspect of this invention is a pharmaceutical composition of matter for treating dopamine deficiency that comprises at least one L-dopa ester as described above, mixtures of L-dopa esters thereof, and/ or pharmaceutical salts thereof, and pharmaceutically acceptable carriers therefor.
  • Such compositions are prepared in accordance with accepted pharmaceutical procedures, for example, as described in Remington 's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pennsylvania, Eighteenth edition (1990).
  • an L-dopa ester as described above, mixtures of L-dopa esters thereof, and/ or pharmaceutical salts thereof, and pharmaceutically acceptable carriers therefor.
  • L-dopa ester, or its salt can be conveniently administered in the form of a pharmaceutical composition containing an L-dopa ester, or its salt, and a pharmaceutically acceptable carrier therefor.
  • Suitable carriers are well known to those skilled in the art and vary with the desired form and mode of administration of the pharmaceutical composition.
  • the carrier may be a liquid, suspension, semi-solid, or vaporizable carrier, or combinations thereof.
  • the carrier is a pharmaceutically acceptable aqueous carrier.
  • the compound of the invention or its salt may be formulated together with the carrier into any desired unit dosage form.
  • Unit dosage forms such as solutions, suspensions, and water-miscible semisolids are particularly preferred.
  • Each carrier must be "acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient.
  • the carrier must be biologically acceptable and inert, i.e., it must permit the body's metabolic reactions to effectively transform the esters of this invention into dopamine.
  • solutions and suspensions are sterilized and are preferably isotonic to blood.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art. Such methods include the step of bringing the active ingredient into association with the carrier which itself may encompass one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Various unit dose and multidose containers e.g., sealed ampules and vials, may be used, as is well known in the art.
  • formulations of this invention may also include other agents conventional in the art for this type of pharmaceutical formulation.
  • Also part of this invention is a method of treating dopamine deficiency, particularly that associated with Parkinson's disease, in a mammal, e.g. human, by treating that mammal with an effective amount of an L-dopa ester intranasally.
  • patient will encompass any mammal suffering from dopamine deficiency, particularly a mammal suffering from Parkinson's disease, or a mammal suffering damage to the substantia nigra of the brain and needing treatment.
  • the dosage of the L-dopa esters, pharmaceutically acceptable salts thereof, or mixtures thereof, in the compositions of the invention administered to a patient will vary depending on several factors, including, but not limited to, the age, weight, and species of the patient, the general health of the patient, the severity of the symptoms, whether the composition is being administered alone or in combination with other agents, the incidence of side effects and the like.
  • the desired dose may be administered as 1 to 6 or more subdoses administered at appropriate intervals throughout the day.
  • the compounds may be administered repeatedly over a period of months or years, or it may be slowly and constantly infused to the patient. Higher and lower doses may also be administered.
  • the daily dose may be adjusted taking into account, for example, the above-identified variety of parameters.
  • the present compositions may be administered in an amount of about 0.1 to 1.0 mg/kg body weight/day. However, other amounts may also be administered.
  • the active compounds may be administered, for instance, by intranasal administration of an approximate 0.1 to IM solution of the active ingredient, optionally in saline.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferably present as a pharmaceutical formulation.
  • the formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • the above method may be practiced by administration of the compounds by themselves or in a combination with other active ingredients in a pharmaceutical composition.
  • Other merapeutic agents suitable for use herein are any compatible drugs that are effective by the same or other mechanisms for the intended purpose, or drugs that are complementary to those of the present agents.
  • the compounds utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times than the present compounds, e.g., sequentially, such that a combined effect is achieved.
  • the amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained.
  • the therapeutic method of die invention may be used in conjunction with other therapies as determined by the practitioner.
  • the prodrug esters of L-dopa may be prepared using a modification of me procedure reported by Patel and Price 35 .
  • One hundred ml of the appropriate alcohol are placed in a 200-ml three-necked flask equipped with a reflux condenser. The alcohol was cooled to -10 * C and nitrogen was bubbled through for 10 min. Thionyl chloride (15 ml) was then added slowly over 15 min, and the reaction mixture was stirred for an additional 15 min. After stirring, 4 g of L-dopa was added, and the mixmre was refluxed at 60 "C for 12 hr.
  • ester hydrochloride was precipitated by adding enough petroleum ether to make the solution turbid and then placing the mixture in a refrigerator(4"C) overnight. The final product was collected by filtration and was recrystallized from an acetone-petroleum ether mixture. The crystals were dried in a vacuum desiccator at room temperature and stored in a desiccator until used. The structure and purity of each ester hydrochloride of L-dopa was confirmed by NMR spectra, HPLC, melting point, and elemental analysis. Examples of esters synthesized using this procedure may be found in Table 2, below.
  • Solvent Delivery Module Spectroflow 757 Absorbance Detector, Spectra-Physics DataJet Integrator, Waters 712 WISP Autoinjector, Waters Nova-Pak C 8 column
  • the mobile phase consisted of 0.05M phosphate buffer at pH 4.0 and acetonitrile.
  • the acetonitrile portion was adjusted according to the ester (see below).
  • the flow rate was set at 1.0 ml/min.
  • the UV wavelength was set at 280nm.
  • L-dopa and its methyl ester the portion of acetonitrile was 0.
  • the retention time was 1.6 minutes for L-dopa and 11.5 minutes for the methyl ester.
  • the portion of acetonitrile was 25%.
  • the retention time was 7 minutes for the butyl ester, 17 minutes for the pentyl ester, 11 minutes for the benzyl ester, and 15 minutes for the cyclohexyl ester.
  • the reactions were initiated by preparing 0.2 mg/ml solutions of the butyl ester prodrug in 0.05M, 0.20M, and 0.50M phosphate buffers at pHs 3.5, 5.5, and 7.4.
  • the solution was kept in screw-capped culture tubes at 20'C and 37"C.
  • the other prodrugs were studied in pH 7.4, 0.05M phosphate buffer at 37'C.
  • the rate of hydrolysis of each ester was determined from the slope of the linear plot of the logarithm of the residual ester concentration against time.
  • the experiments were run at least in triplicate for each ester. The pH was determined after each experiment.
  • the rate constants were calculated and the activation energy was obtained.
  • the pH of optimum stability and the shelf-life at that pH was calculated.
  • the apparent partition coefficient of each ester was determined at room temperature (20"C) between 1-octanol and pH 7.4, 0.05M phosphate buffer.
  • the phosphate buffer and octanol were presaturated with one another before use to minimize the volume change due to mutual solubility.
  • An aqueous phase (5 ml) containing 0.4 mg/ml ester prodrug solution was mixed widi 5 ml of 1- octanol. The mixture was manually shaken for 2 min followed by mechanical shaking at 20 "C for 1 hour to ensure equilibrium. After centrifugation, the ester concentration in the aqueous phase was measured by HPLC.
  • the partition coefficient was calculated by subtracting die final aqueous phase concentration from the initial aqueous phase concentration to calculate the final octanol phase concentration. The partition coefficient was then calculated by dividing the final aqueous phase concentration into the final octanol phase concentration.
  • Table 2 lists the physicochemical properties of L-dopa, L-dopa prodrugs, and dopamine. The partition coefficients were measured between octanol and pH 7.4, 0.05M phosphate buffer at 20 'C.
  • the prodrugs are significantly more soluble and more lipophilic than L-dopa itself. Based on the desirable physicochemical properties of the butyl ester, this compound was chosen for the nasal abso ⁇ tion studies.
  • Tables 4 and 5 summarize the results of the degradation studies of L-dopa butyl ester in 0.05M, 0.20M and 0.50M phosphate buffer at pH 3.5, 5.5 and 7.4 at 20'C and 37'C.
  • HPLC system for in-vitro enzymatic studies also included: Applied Biosystems Solvent Delivery System 400, Fluorescence Detector 980; ABI Analytical Kratos Division Spectroflow Static Mixer/Injector model 491; SpectraPhysics DataJet Integrator; Shimadzu Auto-Injector SIL-6A, Whatman Partisil 5 SCX column (4.6 mm x 100 mm), Whatman CO:PEL ODS Guard column (2 mm x 70 mm).
  • the mobile phase consisted of 0.05M phosphate buffer at pH 2.6, and acetonitrile, containing ethylenediammetetraacetic acid disodium salt dehydrate 20 mg/1.
  • the acetonitrile portion was adjusted according to the ester (see below).
  • the flow rate was set at 1.0 ml/min.
  • the excitation wavelength was set at 282 nm and me emission wavelength was set at 310 nm.
  • the rate of hydrolysis of each ester was determined from the slope of the linear plot of the logarithm of the residual ester concentration against time.
  • rat brain tissue was homogenized with 5 parts of saline using a tissue grinder.
  • Five 200 ⁇ l aliquot parts of brain homogenate were added to five 100 ⁇ l of a 0.05M, pH 6.0 phosphate buffer solution containing 1 mg/ml of the appropriate ester and incubated at 37'C.
  • the reactions were quenched at various times by adding 200 ⁇ l of acetonitrile.
  • the samples were centrifuged for 2 minutes. The supernatant was filtered through a 0.45 pm filter and injected directly onto the HPLC.
  • the rate of hydrolysis of each ester was determined from the slope of the linear plot of the logarithm of the residual ester concentration against time.
  • rat CSF Five 50 ⁇ l aliquot parts of rat CSF were added to five 50 ⁇ l of a 0.05M, pH 6.0 phosphate buffer solution containing 1 mg/ml of the butyl ester and die samples incubated at 37 X. The reactions were quenched at various times by adding 200 ⁇ l of acetonitrile. The samples were centrifuged for 2 minutes. The supernatant was filtered through a 0.45 pm filter and injected directly into the HPLC.
  • the rate of hydrolysis of butyl ester was determined from the slope of me linear plot of the logarithm of the residual ester concentration against time.
  • Nasal perfusate was obtained from the rat nasal cavity by circulating 3 ml of saline into one nostril and collecting the saline solution from the other nostril. Circulating time was 3 minutes.
  • the hydrolysis study was performed immediately following perfusion. Five 200 ⁇ l aliquot parts of rat nasal perfusate were added to five 100 ⁇ l of a 0.05M, pH 6.0 phosphate buffer solution containing 1 mg/ml of the butyl ester and the samples incubated at 37'C. The reactions were quenched at various times by adding 200 ⁇ l of acetonitrile. The samples were centrifuged for 2 minutes. The supernatant was filtered through a 0.45 ⁇ m filter and injected directly into die HPLC. The rate of hydrolysis of butyl ester was determined from the slope of the linear plot of the logarithm of the residual ester concentration against time. Results
  • Table 6 summarizes the half lives of several esters of L-dopa in rat plasma and rat brain homogenate. The half lives for the hydrolysis of the butyl ester in rat CSF and nasal perfusate are also reported in Table 6.
  • HPLC system for in vivo studies included: Applied Biosystems Solvent Delivery System 400, Applied Biosystems 429A Integrator, ABI Analytical Kratos Division Spectroflow Static mixer/Injector model 591; BAS Amperometric Detector LC-4B (operated at +0.8 V vs. a Ag/AgCl reference electrode), TOSOH TSK-GEL ODS-80Tm column (4.6 mm x 150 mm), Whatman CO: PEL ODS Guard column (2 mm x 70 mm).
  • L-dopa and dopamine were measured in plasma, brain, and cerebrospinal fluid (CSF) by a previous reported high performance liquid chromatographic (HPLC) procedure using an electrochemical detector 36 , with a slight modification.
  • the mobile phase consisted of 0.05M phosphate buffer at pH 2.9, heptane sulfonate sodium salt 500 mg/1, and ethylenediaminetetraacetic acid disodium salt dehydrate 15 mg/1.
  • the flow rate was set at 1.5 ml/min.
  • the retention times were 13 minutes for L-dopa, 17 minutes for dihydroxyphenylamine(internal standard) and 29 minutes for dopamine.
  • Male Sprague-Dawley rats weighing 250-275 gm were used.
  • the cavity was washed with 2 ml of 0.05M, pH 6.0 phosphate buffer.
  • the dopamine concentration was determined by HPLC.
  • Ester prodrugs solutions at 4, 20, and 40 mg/kg/0.2 ml equimolar doses of L-dopa were freshly prepared by using 0.05M phosphate buffer at pH 6.0. Solutions of L-dopa were prepared by first dissolving the compound in IN hydrochloric acid then using 0.5M phosphate buffer at pH 7.4 to adjust the solution to pH 4.
  • Solutions for dopamine were prepared at 20mg/kg/0.2ml by using 0.05M phosphate buffer at pH 6.0.
  • aqueous solutions of L-dopa or equimolar prodrugs were administered dirough me nostril using a microsyringe.
  • intravenous administration the same dose of the drug was injected through the jugular vein.
  • Plasma samples were mixed with 5 ⁇ l of 2% Na 2 EDTA and 5 ⁇ l of 5% sodium metabisulfite in normal saline. The samples were kept frozen until extraction. L-d ⁇ d as iioi ted y a modification of die alumina adsorption procedure of A.H. Anton 34 . (Alumina activation was mentioned in Section 4.1) Each plasma sample (50 ⁇ l) was mixed with 70 mg of activated aluminum gel, 0.2 ml of 2M Tris buffer (pH 8.6), 0.1 ml of 2N NaOH, and 10 ⁇ l of 3,4- dihydroxybenzylamine aqueous solution as an internal standard in a glass test- tube for 30 min.
  • the alumina was washed once wim 8 ml of lOmM Tris buffer (pH 8.6) and twice with 8 ml of distilled water adjusted to pH 7.0 with 0.1N NaOH. After the water was aspirated, L-dopa was eiuted with 0.3 ml of 0.8N HCI. The samples obtained were frozen until HPLC analysis.
  • FIG. 19 shows plasma L-dopa levels after nasal administration of L-dopa and me prodrugs at a dose of 4 mg/kg L-dopa equivalent.
  • FIG. 21 shows the plasma level profiles following the nasal and intravenous administrations of me butyl ester at the 20 mg/kg L-dopa equivalent dose.
  • the AUCs were calculated to be 584.29 ⁇ g/ml*min for the intravenous route and 521.55 ⁇ g/ml*min for the nasal route.
  • the nasal bioavailability is about 89.3 % of that of the intravenous administration.
  • Dopamine was found to be rapidly eliminated following intravenous administration as shown in Figure 23.
  • the elimination rate constant was found to be 10 times faster than that of L-dopa and was estimated to be 0.118 min 1 .
  • the nasal abso ⁇ tion of dopamine was found to be relatively slow and incomplete as shown in Figure 23.
  • the abso ⁇ tion phase was long and at die end of experiment, about 68% of die administered dose was recovered from the nasal cavity.
  • Such a slow rate of abso ⁇ tion could not be attributed to the partition coefficient, since the partition coefficient of L-dopa in die same solvent system is similar to that of dopamine. It may be possible that dopamine retards its own abso ⁇ tion due to its vasoconstrictive effect.
  • the cerebrospinal fluid and olfactory bulb concentrations of L-dopa following the intravenous and nasal administration of the butyl ester at 20 mg/kg L-dopa equivalent dose are shown in Figure 24 and Figure 25. It is evident that the cerebrospinal fluid and the olfactory bulb have higher concentrations of L-dopa following nasal administration than following intravenous administration. These data suggest diat the butyl ester can reach the CSF or olfactory bulb via a direct pathway.
  • Table 7 Relationship of the partition coefficients and L-dopa levels in the plasma, CSF and olfactory bulb following nasal administration
  • D Concentration of dopamine in rat plasma
  • k ! Abso ⁇ tion rate constant for the butyl ester of L-dopa from the rat nasal cavity
  • k 2 Hydrolysis rate constant from butyl ester to L-dopa
  • k 3 Metabolism rate constant from L-dopa to dopamine
  • k j Metabolism rate constant for dopamine
  • a Q 6000 ⁇ g, the initial dose
  • I 0.1177 min "1 , rate of elimination of dopamine.

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Abstract

L'estérification du groupe carboxylique du lévodopa a abouti à des dérivés (des bioprécurseurs) qui sont considérablement plus hydrosolubles et plus lipophiles que le lévodopa. On a constaté que ces esters: a) sont rapidement absorbés à partir de la cavité nasale du rat, b) sont rapidement hydrolysés en lévodopa dans le plasma, le broyat de cervelle et le liquide céphalorachidien (LCR) du rat, c) s'éliminent après administration nasale et intraveineuse à une vitesse correspondant à celle du lévodopa (t1/2 = 63,0 minutes), et d) sont relativement stables en solutions aqueuses, particulièrement à des pH inférieurs à 5,0. L'administration par voie intranasale à l'homme de bioprécurseurs du lévodopa minimise les effets secondaires périphériques associés à l'administration de lévodopa par voie orale. L'utilisation de bioprécurseurs hydrosolubles du lévodopa administrés par voie nasale présente des avantages thérapeutiques pour le traitement de la maladie de Parkinson étant donné que l'administration par voie nasale ne provoque pas de formation notable de dopamine dans la circulation périphérique, et que cette voie d'administration permet d'administrer le lévodopa effectivement dans la circulation sanguine.
PCT/US1996/017740 1995-11-03 1996-11-04 Administration par voie intranasale de bioprecurseurs du levodopa WO1997016181A1 (fr)

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Cited By (16)

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WO1999001229A1 (fr) 1997-07-01 1999-01-14 Gjerding Peter Procede d'administration de substances actives a l'aire olfactive
US6737042B2 (en) 2001-05-24 2004-05-18 Alexza Molecular Delivery Corporation Delivery of drug esters through an inhalation route
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US7581540B2 (en) 2004-08-12 2009-09-01 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US7585493B2 (en) 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
WO2009129497A2 (fr) 2008-04-18 2009-10-22 Arizona Board Of Regents, A Body Corp. Of The State Of Arizona, Acting For And On Behalf Of The University Of Arizona Methodes et compositions de traitement de la degenerescence maculaire liee a l’age et d’identification de composes appropries
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9849104B2 (en) 2015-11-06 2017-12-26 Gemphire Therapeutics Inc. Treatment of NASH with gemcabene
CN113164494A (zh) * 2018-09-28 2021-07-23 格里菲斯大学 用于调节病原体活性的剂和方法
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US11969401B2 (en) 2019-01-31 2024-04-30 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treating or limiting development of age-related macular degeneration
US12214119B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device
EP4329722A4 (fr) * 2021-04-28 2025-03-26 Univ Southern California Utilisation d'alcool périllylique pour améliorer l'administration de levo-dopa

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US5354885A (en) * 1992-12-24 1994-10-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Process for preparing ethyl ester of L-DOPA

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Publication number Priority date Publication date Assignee Title
WO1999001229A1 (fr) 1997-07-01 1999-01-14 Gjerding Peter Procede d'administration de substances actives a l'aire olfactive
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US6737042B2 (en) 2001-05-24 2004-05-18 Alexza Molecular Delivery Corporation Delivery of drug esters through an inhalation route
US7070765B2 (en) 2001-05-24 2006-07-04 Alexza Pharmaceuticals, Inc. Delivery of drug esters through an inhalation route
US7078019B2 (en) 2001-05-24 2006-07-18 Alexza Pharmaceuticals, Inc. Delivery of drug esters through an inhalation route
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US10350157B2 (en) 2001-05-24 2019-07-16 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9440034B2 (en) 2001-05-24 2016-09-13 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US7585493B2 (en) 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
US11065400B2 (en) 2001-06-05 2021-07-20 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US7581540B2 (en) 2004-08-12 2009-09-01 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US12138383B2 (en) 2007-03-09 2024-11-12 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US9861600B2 (en) 2008-04-18 2018-01-09 Arizona Board of Regents, A Body Corporate Of The State Of Arizona Acting For An On Behalf Of The University of Arizona Methods and compositions for treating and identifying compounds to treat age-related macular degeneration treatment
WO2009129497A2 (fr) 2008-04-18 2009-10-22 Arizona Board Of Regents, A Body Corp. Of The State Of Arizona, Acting For And On Behalf Of The University Of Arizona Methodes et compositions de traitement de la degenerescence maculaire liee a l’age et d’identification de composes appropries
US9173862B2 (en) 2008-04-18 2015-11-03 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of The University Of Arizona Methods and compositions for treating and identifying compounds to treat age-related macular degeneration
US10449154B2 (en) 2015-11-06 2019-10-22 Gemphire Therapeutics Inc. Treatment of NASH with Gemcabene
US9849104B2 (en) 2015-11-06 2017-12-26 Gemphire Therapeutics Inc. Treatment of NASH with gemcabene
US12214119B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device
US12214118B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device
CN113164494A (zh) * 2018-09-28 2021-07-23 格里菲斯大学 用于调节病原体活性的剂和方法
US11969401B2 (en) 2019-01-31 2024-04-30 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treating or limiting development of age-related macular degeneration
EP4329722A4 (fr) * 2021-04-28 2025-03-26 Univ Southern California Utilisation d'alcool périllylique pour améliorer l'administration de levo-dopa

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