Classifications

• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

• the present invention relates to a stable sustained release injectable formulation of levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof, a process for the manufacture of this formulation and the use of the formulation to control hypothyroidism.
• Levothyroxine is a hormone and was first isolated in crystalline form in 1915. Its structural formula was discovered in 1926 and it was first synthesized in 1927.
• the thyroid gland produces hormones that regulate the metabolism of living organisms. Several disorders exist which may lead to the thyroid gland being overactive (hyperthyroidism) or underactive (hypothyroidism), the most common being Hashimoto’s disease, Grave’s disease, goitre and thyroid nodules. Common hypothyroid symptoms include fatigue, weight gain, inability to tolerate cold, slow heart rate, dry skin and constipation.
• Levothyroxine in oral form is typically used to treat thyroid hormone deficiency such as hypothyroidism and thyroid tumours and used to treat or prevent goitre, often taking the levothyroxine as a lifelong therapy.
• thyroid hormone deficiency such as hypothyroidism and thyroid tumours
• goitre often taking the levothyroxine as a lifelong therapy.
• myxedema coma the levothyroxine may be administered intravenously with an initial loading dose, followed by a daily intravenous maintenance dose until the levothyroxine levels are controlled.
• Intravenous formulations have been used as early as the 1960’s.
• Levothyroxine microparticles for topical and transdermal delivery have been prepared in a study published in Biopharm. Drug Dispos. 32: 380-388, 2011. Those were prepared in various polymer matrices, i.e. poly D,L lactide (PLA), poly(lactic-co- glycolic acid) (PLGA), poly(N-isopropylacrylamide) (PNTPAM) and ethyl cellulose (EC).
• PDA poly D,L lactide
• PLGA poly(lactic-co- glycolic acid)
• PNTPAM poly(N-isopropylacrylamide)
• EC ethyl cellulose
• a sustained release pharmaceutical formulation comprising microparticles of levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof with a poly(D,L-lactide-co-glycolide) polymer, wherein the formulation has a theoretical levothyroxine loading of at least 1.5%w/w is provided, which overcomes the deficiencies of the prior art and provides a relatively low initial burst release of levothyroxine and a sustained rate of release over an extended period of time.
• TDL The theoretical drug loading
• Further object of the present invention is to provide an injectable controlled release formulation comprising levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof, which shows good syringeability, injectability, no clogging or blockage of the syringe needles, good drainage, sterility and re-suspensibility
• a further advantage of the present invention is the formulation of levothyroxine can increase patient compliance to medication and replace the existing treatment regimens which require frequent (daily) oral or injection dosing.
• the present invention provides a pharmaceutical formulation for intramuscular or subcutaneous administration, in a single or at multiple injection sites, comprising levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof, as an active ingredient, which is able to offer pharmacological effect for at least a week and up to two months with a single administration.
• the formulation may be administered from once every month to once every two months, preferably once every month or once every two months.
• the present invention further includes sterile injectable controlled release formulations comprising levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof, in the form of ready to use solutions, ready to use suspensions and suspensions/solutions formed by reconstitution with a suitable diluent just before administration (injection).
• a further aspect of the present invention provides a fast, simple and cost-effective process for the preparation of a stable injectable pharmaceutical formulation comprising levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof.
• Microparticles or “microspheres” are particles comprising a polymer that serves as a matrix or binder of the particle.
• the microparticle may contain an active compound dispersed or dissolved in the polymeric matrix and is biodegradable and biocompatible.
• Biodegradable materials are those that degrade by bodily processes to products readily disposable by the body and should not accumulate in the body.
• Biocompatible means not toxic to the body, pharmaceutically acceptable, not carcinogenic and which does not significantly induce inflammation in body tissues.
• “By weight %” means parts by weight per total weight of the microparticle.
• sustained release formulation a pharmaceutical dosage form which provides continuous release of the active pharmaceutical ingredient for a sustained period of time of few days to several months with a single administration.
• PLGA is poly(lactic-co-glycolic acid) copolymer.
• the molecular weight of a synthetic polymer does not have a single value, since different chains will have different lengths and different numbers of side branches. There will therefore be a distribution of molecular weights, so it is common to calculate the “average molecular weight” of the polymer.
• active agent refers to the pharmacologically active compound of the present invention which is Levothyroxine or it’s pharmaceutically acceptable salts, derivatives or metabolites thereof. With the same meaning the term Levothyroxine is used interchangeably throughout the current specification.
• Erosion is defined as the physical dissolution of a polymer as a result of its degradation.
• extraction factor g is defined as:
• an object of the present invention is to provide a sustained release injectable formulation of levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof to overcome the issues of the existing thyroid therapies, providing a uniform and constant release rate over an extended period of time.
• the formulation comprises levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite levothyroxine and preferably comprises levothyroxine or a pharmaceutically acceptable salt hydrated or anhydrous.
• the formulation comprises a pharmaceutically acceptable salt the salt is selected from sodium, potassium and the like, preferably sodium.
• Levothyroxine or it’s pharmaceutically acceptable salts, derivatives or metabolites thereof are generally hydrophobic or amphiphilic and insoluble in solvents commonly used to form polymer solutions, thus it is challenging to formulate levothyroxine into matrix polymers.
• another object of the present invention is to provide a process for preparing the levothyroxine microparticles of the invented formulation.
• a further object of the present invention is to provide a sustained release injectable formulation of levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof with a drug loading suitable to satisfy the maximum dosing requirements.
• Yet a further object of the present invention is to provide a sustained release injectable formulation of levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof that exhibits release over an extended period of time, preferably release over a period ranging from 1 week to 2 months, more preferably over a period from 1 to 2 months when injected subcutaneously or intramuscularly while at the same time has no or only a short period passes before release initiation (lag phases) and exhibits low initial burst release compared to the typical values.
• Lag phases are typically up to 10 days and initial burst release is less than 40% of the total levothyroxine in the microspheres.
• the levothyroxine microparticles of the sustained release injectable formulation are manufactured by single emulsion process.
• the PLGA polymer is dissolved in a suitable solvent including, but not limited to di chloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, hexafluoroisopropanol, chloroform or acetone, or a combination thereof to form a PLGA polymer solution.
• suitable solvents include methanol for the sodium salt form of levothyroxine to form a levothyroxine solution.
• a dispersed (oil) phase is prepared by mixing the PLGA polymer solution and the levothyroxine solution resulting in a cosolvent system where both PLGA and Levothyroxine are soluble.
• a process for preparing a sustained release pharmaceutical formulation for intramuscular or subcutaneous administration comprising levothyroxine or a pharmaceutically acceptable salt, derivative or metabolite thereof, as an active ingredient, is also provided.
• Levothyroxine in the formulations of the present inventions is preferably levothyroxine or a pharmaceutically acceptable salt, more preferably levothyroxine sodium hydrated or anhydrous.
• the formulation of the present invention comprises the active pharmaceutical ingredient, a vehicle, other pharmaceutically acceptable excipients and pH adjusting agent(s).
• the order of mixing the constituents of the formulation is interchangeable.
• a general preferred process for the preparation of microparticles comprises the following steps:
• DP dispersed phase
• the dispersed and the continuous phases are mixed and emulsified using a high shear rotor-stator continuous flow disperser (i.e., in line homogenizer) or an overhead stirrer to form a suspension;
• a high shear rotor-stator continuous flow disperser i.e., in line homogenizer
• an overhead stirrer to form a suspension
• the DP is emulsified in the CP with vigorous stirring
• the suspension is subjected to solvent extraction and evaporation by stirring under controlled temperature at 5 - 25°C and air flow to ensure removal of organic solvents and particle solidification;
• microparticles are collected on a glass filter dryer, washed with an excess of water at room temperature and left under vacuum for 24 hours to dry
• PLGA is dissolved in dichloromethane under stirring.
• Levothyroxine sodium is dissolved (under stirring) in methanol and is then added to the polymer solution under stirring to form the dispersed phase.
• the dispersed phase is kept under a controlled temperature at 5 °C to 25 °C, preferably at 5 - 10 °C.
• the levothyroxine sodium and PLGA polymer mixture (oil or dispersed phase) formed is subsequently emulsified into an aqueous or continuous phase comprising an aqueous solution of a surfactant, the surfactant is preferably an aqueous solution of polyvinyl alcohol (PVA).
• PVA polyvinyl alcohol
• levothyroxine sodium and the PLGA polymer mixture is emulsified in a PVA aqueous solution.
• the emulsification is preferably performed with a high shear rotor-stator continuous flow disperser (such as in line homogenizer) or an overhead stirrer.
• the emulsion is then transferred into a receiving tank and remains under controlled temperature, air flow and stirring conditions to remove the organic solvent.
• the suspension is thermostated at a temperature lower than 20 °C, more preferably 5 - 10 °C for 3 to 4 hours.
• a microparticle suspension is formed which is filtered through a glass filter dryer to collect the microparticles with the desired particle size.
• the microparticles are then washed on the glass filter dryer with an excess of water at room temperature and left under vacuum for 24 hours to dry.
• the process of the present invention provides microparticles with a particle size distribution of from 10-200 microns as measured by laser light diffraction.
• the solubility at 20 °C of the API in MeOH was determined as follows: approximately 50 mg Levothyroxine sodium were weighed in a vial. Methanol was gradually added until the solution became clear. The solubility was determined at 3.41% mass LVX/mass of MeOH.
• a quantity of approximately 0.25 g of polymer and varying quantities of LVX corresponding to theoretical drug loading values 1%, 2%, 3% and 4% were weighed in four vials.
• a DCM/MeOH mixture at a ratio of 10/3 (to ensure the polymer is always dissolved) was gradually added in each vial.
• the respective PLGA (PURASORB PDLG 5002A) concentrations, % LVX content and LVX solubility were evaluated and are presented in the table below.
• the PLGA concentration will have to be lower than 3% which is too low for the formulation of microparticles.
• the PLGA (PURASORB PDLG 5002A) concentration was set at 5% in DCM (3.8% in the DCM+ MeOH mixture).
• the theoretical drug loading values in the formulation range between 1.5 and 3%.
• Such theoretical drug content of at least 1.5%, preferably from 1.5% to 3.0% and more preferably from 2% to 3% and g factor from 1 to 1.5 lead to microparticles with a release of at least one month with low initial lag phase according to the present invention. Levothyroxine microparticles of lower theoretical drug loading do not release for adequate time.
• PLGA polymers of higher MW and higher lactide-to-glycolide ratio results in a release profile that is considered too slow for the purposes of this invention.
• Levothyroxine is preferably dissolved in methanol, preferably when the mass of Levothyroxine to the mass of MeOH is about 3.41%. Additionally, the PLGA is particularly preferred to be dissolved in DCM and the ratio of Levothyroxine to the combined mass of DCM plus MeOH is below 0.1%.
• PLGA is a linear aliphatic copolymer obtained at different proportions between its constituent monomers, lactic acid (LA) and glycolic acid (GA). It can be synthesized with any ratio of LA and GA, molecular weights (Mw) with a wide range from below 10,000 up to 200,000 g/mol and in completely amorphous or highly crystalline forms. The amorphous form is found to be suitable for drug release as it provides more even dispersion of a payload in the polymer matrix. The release and degradation rate are profoundly affected by the Mw and the LA/GA ratio. Generally, polymers with higher Mw retain more structural integrity due to cross-linking and exhibit longer release profiles. PLGAs with high GA content are more hydrophilic and allow higher water permeability, resulting in faster degradation rates while at the same time exhibit higher degree of crystallinity.
• PLGA polymers are commercially available from various sources and easily customizable to the needs of any customer.
• Exemplary commercially available PLGA polymers that may be used in the present invention are Resomer®, Medisorb®, Expansorb® and Purasorb® PDLG. These polymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid, and different polymer chain end groups.
• the inventors of the present invention found that PLA used in the prior art sustained release levothyroxine injectable formulation has a slow rate of degradation, leading to a very slow drug release.
• the PLGA polymers suitable for the presently claimed levothyroxine sustained release injectable formulations has a lactide to glycolide ratio of from 80:20 to 20:80, more preferably from 75:25 to 25:75and most preferably from 75:25 to 50:50.
• Particularly preferred PLGA polymers are those with a lactide to glycolide ratio of 50:50 and 75:25.
• PLGA polymer average molecular weight (M w ) are preferably in ranges between 5 kDa to 200 kDa, more preferably 15 - 120 kDa. Particularly preferred PLGA polymers are those with average molecular weights of 18k Da and 115kDa.
• the sustained release injectable formulation of the present invention comprises microparticles which comprise levothyroxine or a levothyroxine salt, preferably the sodium salt and a polymer, preferably PLGA, is disclosed.
• Levothyroxine or levothyroxine sodium may be present in a 1.0-5.0 wt% concentration, more preferably 1.5-3.0 wt%, while PLGA concentration may range between 99.0 and 95.0 wt%, preferably 97 0 and 98 5 wt%. Most preferably, levothyroxine is present in a 2.5% concentration and PLGA in a 97.5% concentration.
• the PLGA molecular weight is determined by comparison with Gel Permeation Chromatography (GPC) polystyrene (PS) calibration standards (M w range 3-200 KDa).
• GPC Gel Permeation Chromatography
• PS polystyrene
• the retention time values of the standard solutions in combination with the MW value of their CoAs are used to create the calibration curve depicting the retention time vs log(M w ).
• the retention time of the sample is translated to molecular weight based on the calibration curve.
• the calibration curve is a 3 rd order expression of the retention time vs log(M w ) calculated by the GPC software.
• the in vitro release of the drug from the microparticles of the present invention is studied in phosphate buffer saline solutions at various pH values.
• the formulation microparticles are suspended in a phosphate buffer saline release medium and incubated in a water bath system at 37°C. At given time intervals, samples are taken and the amount of drug released is measured by HPLC.
• the microparticles of the present invention are reconstituted prior to injection to form a suspension.
• the suspension comprises the microparticles and a medium (diluent), the medium can be aqueous or non-aqueous.
• the suspension may also comprise one or more solubilizing or wetting agents, one or more flocculating or suspending agents, one or more antimicrobial preservatives, one or more antioxidants, one or more buffering agents, one or more pH adjusting agents, one or more tonicity adjusting agents, and one or more chelating agents.
• solubilizing agents examples include diethylene glycol monostearate, diethylene glycol monolaurate, glyceryl monostearate, polyoxyethylene sorbitol beeswax, polyethylene lauryl ether, polyoxyethylene leuryl ether, polyoxyethylene monostearate, polyoxyethylene alkyl phenol, polyethylene sorbitan monooleate, polyethylene sorbitan monolaurate, polyoxyethylene lauryl ether, potassium oleate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sodium lauryl sulfate, sodium oleate, triethanolamine oleate, etc.
• Pol oxamer and Lutrol® Fl 08 are particularly preferred as solubilizing or wetting agents
• Sodium carboxymethylcellulose and hydroxypropylmethylcellulose are particularly preferred as flocculating or suspending agents.
• antioxidants examples include acetone sodium bisulfate, ascorbate, a-tocopherol, bisulfate sodium, butylated hydroxy anisole, butylated hydroxy toluene, cystein, cysteinate HC1, dithionite sodium, gentisic acid, gentisic acid athanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol, propyl gallate, sulfite sodium, tocopherol alpha, thioglycolate sodium etc.
• Butylated hydroxyl anisole and/or bisulfite are particularly preferred as antioxidants.
• a buffer is optionally employed.
• suitable buffers include: sodium phosphate, potassium phosphate, sodium hydroxide, succinate sodium, succinate disodium, sulfuric acid, tartrate sodium, tartaric acid, tromethamine.
• Sodium phosphate is particularly preferred as buffering agent.
• pH adjusting agents in order to adjust the pH of the suspension from about 6 to about 8, preferably about 7, may be present as well.
• the pH adjusting agents may be either an acid or a base.
• Examples of pH adjusting agents suitable for use in the present invention include acetic acid, calcium carbonate, hydrochloric acid, magnesium oxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide etc. Sodium hydroxide and hydrochloric acid are particularly preferred as pH adjusting agents.
• one or more tonicity adjusting agents is optionally used.
• suitable tonicity adjusting agents include magnesium sulfate, maltose, mannitol, polyethylene glycol, polylactic acid, polysorbate, potassium chloride, povidone, sodium chloride, sodium cholesteryl sulfate, sodium succinate, sodium sulfate, sorbitol, sucrose, trehalose.
• Sodium chloride is particularly preferred as the tonicity adjusting agent.
• the suspension may optionally include one or more chelating agents.
• suitable chelating agents include calcium disodium ethylenedi aminetetraacetic acid (EDTA), disodium EDTA, sodium EDTA and diethylenetriaminepentaacetic acid (DTP A), citric acid, tartaric acid and amino acids, such as lysine and arginine, can also act as chelating agents.
• EDTA calcium disodium ethylenedi aminetetraacetic acid
• DTP A diethylenetriaminepentaacetic acid
• citric acid tartaric acid
• amino acids such as lysine and arginine
• the sustained release formulations of the present invention may be used to control hypothyroidism in adults, congenital hypothyroidism in infants and acquired hypothyroidism in children.
• the formulation may be further used as replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.
• Specific indications include primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism.
• Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.
• the formulation may be used in the treatment or prevention of various typed of euthyroid goiters including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin dependent well-differentiated thyroid cancer.
• euthyroid goiters including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin dependent well-differentiated thyroid cancer.
• the formulations are preferably administered by subcutaneous or intramuscular injection after being reconstituted with suitable diluent. More particularly formulations may be presented as a kit in which the diluent is packed in a pre-filled syringe and the microparticles are in a vial. Immediately before use the content of the pre-filled syringe (diluent) and the vial (powder) are mixed to prepare the suspension to be injected to the patient.
• a dual chamber syringe may be used; the microparticles are stored in one chamber of the syringe and the diluent stored in the other chamber of the pre-filled syringe, immediately before injections the contents of each chamber are mixed to form a suspension which is injected to the patient.
• Suitable diluents include inactive ingredients such as carboxymethylcellulose sodium, mannitol, sodium chloride, sodium hydroxide, polysorbate, acetic acid, sodium dihydrogen phosphate monohydrate, disodium phosphate heptahydrate.
• the formulations are preferably administered once every one or two months.
• Microparticles were prepared with the process as exemplified in the description above using three types of PLGA polymers, PLTRASORB PDLG 5002A with 18 kDa molecular weight and RESOMER RG 504H with 60 kDa molecular weight, both having lactide to glucolide ratio 50:50 and PURASORB PDLG 7510 with 115 kDa molecular weight and lactide to glucolide ratio 75:25.
• PSD particle size distribution
• Formulations LVX_1.2 and LVX_1.3 exhibit sigmoidal profiles with lag phases of ⁇ 10 and 20 days respectively followed by a main release phase up to ⁇ day 25 and day 40 respectively.
• LVX 1.5 and LVX 1.6 Two formulations (LVX 1.5 and LVX 1.6) were prepared based on LVX_1.2 and one (LVX_1.12) based on LVX 1.3, introducing changes in the theoretical drug loading and the g factor. Both parameters are increased (theoretical drug content from 1.5% to 2.0 and 3.0% and g factor from 1 to 1.5) aiming at a higher drug content.
• TDL Theoretical Drug loading
• PSD PSD
• Formulations with high MW polymer also exhibit lower initial burst.

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