WO1993009763A1 - Comprime pharmaceutique a pvp ayant une vitesse de dissolution de medicament amelioree - Google Patents

Comprime pharmaceutique a pvp ayant une vitesse de dissolution de medicament amelioree Download PDF

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Publication number
WO1993009763A1
WO1993009763A1 PCT/US1992/009821 US9209821W WO9309763A1 WO 1993009763 A1 WO1993009763 A1 WO 1993009763A1 US 9209821 W US9209821 W US 9209821W WO 9309763 A1 WO9309763 A1 WO 9309763A1
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WO
WIPO (PCT)
Prior art keywords
pvp
initiator
pharmaceutical tablet
tablet
pharmaceutical
Prior art date
Application number
PCT/US1992/009821
Other languages
English (en)
Inventor
Ratan K. Chaudhuri
Dinesh K. Jaiswal
Rama K. Haldar
Robert B. Login
Mohammed Tazi
Jui-Chang Chuang
Original Assignee
Isp Investments Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/796,999 external-priority patent/US5262171A/en
Application filed by Isp Investments Inc. filed Critical Isp Investments Inc.
Publication of WO1993009763A1 publication Critical patent/WO1993009763A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • This invention relates to a pharmaceutical tablet containing polyvinylpyrrolidone (PVP) as a binder for a pharmaceutically-active ingredient therein, and more particularly, to such tablets which dissolve readily in water to release their active material even after the product has experienced a considerable period of PVP.
  • PVP polyvinylpyrrolidone
  • PVP is used widely as a binding agent for pharmaceutical tablets. However, it is essential that the PVP binder itself not interfere with the normal dissolution rate of the tablet in water. Suitable PVP polymers
  • TBPP t-butylperoxy pivalate
  • TBPB t-butylperoxy benzoate
  • TBPP for example, undergoes thermal homolysis to produce t-butoxy and t-butyl free radicals.
  • the choice of initiator is critical to preclude the formation of branched rather than linear PVP polymers both during polymerization and afterwards during ageing of pharmaceutical tablets containing such PVP as a binding agent.
  • a pharmaceutical tablet is provided herein containing a pharmaceutically-active ingredient and a K-30 to K-120, preferably above 116, PVP as a binding agent, suitably about 0.5-10% by weight, preferably about 5%.
  • the PVP is made by a free radical initiated polymerization process in which vinylpyrrolidone monomer is polymerized in the presence of a low energy peroxy radical initiators, such as t-amylperoxy pivalate (TAPP), an azo initiator, or a redox initiator, and at the lowest possible reaction temperatures.
  • a low energy peroxy radical initiators such as t-amylperoxy pivalate (TAPP), an azo initiator, or a redox initiator, and at the lowest possible reaction temperatures.
  • TAPP t-amylperoxy pivalate
  • azo initiator an azo initiator
  • a redox initiator a redox initiator
  • Azo initiators are preferred because they generate free radicals that are of low energy. A similar effect is obtained using a low temperature free radical initiator that has an acceptable half-life at lower temperatures because the rate expression for transfer to polymer is dependent on temperature.
  • the low transfer to polymer property of these initiators enable the residual initiator to be decomposed at elevated temperatures without causing crosslinking.
  • a PVP K-90 polymer mixture prepared in water can be post-heated at 60-80°C. to reduce the residual initiator level to less than 500 ppm.
  • the PVP obtained has a K-value in excess of 116, e.g. 119-140, and a viscosity average molecular weight* of at least one million, a weight average molecular weight** of at least two million, and a relative viscosity*** of at least 1.2, most preferably about
  • the tablet contains a suitable
  • the pharmaceutical tablet consists essentially of, by weight, about 10-98% of poorly water-soluble drug, about 2-10% of PVP K-116-140, about 0.5-2% of a lubricant, 0-3% disintegrant and about 0-85% of a filler, and is prepared either by direct compression or by using wet granulation.
  • the pharmaceutical tablets provided herein are particularly characterized by a rapid dissolution rate even after a prolonged shelf-life; accordingly, the PVP polymer prepared and used herein performs its binding function without an accompanying adverse side effect of a reduced dissolution rate for the active material in the tablet.
  • a free radical polymerization process for polymerizing vinylpyrrolidone to form PVP is provided herein.
  • initiator is, (1) a peroxy ester which radicals are weak hydrogen abstractors, e.g. t-amylperoxy pivalate (TAPP); (2) an azo initiator, or (3) a redox catalyst.
  • TAPP t-amylperoxy pivalate
  • azo initiator or (3) a redox catalyst.
  • TAPP ⁇ TAPP ⁇ peroxy benzoates undergoes thermal homolysis as follows:
  • TAPP are:
  • TAPP is a relatively weak hydrogen abstractor.
  • substantially linear PVP polymers of high molecular weight and excellent water solubility are provided using the TAPP initiator of the invention.
  • polyvinylpyrrolidone formed by free radical polymerization of vinylpyrrolidone has several active hydrogen sites, indicated by the asterisks, for hydrogen abstraction by the active free radical species of TBPP.
  • TAPP and other low energy or poor transfer to polymer initiators, on the other hand, have only weak hydrogen abstractors or are effective for polymerization at low temperatures, and produce substantially linear PVP polymers which exhibit excellent water dissolution, even after ageing. Furthermore, it is known that lower molecular weight polymers are produced when high polymerization temperatures or long reaction periods are required. TAPP, and azo and redox catalysts, can effect PVP polymerizations at lower temperatures, than these more active higher temperature initiators; therefore, it is possible to produce herein high molecular weight, linear PVP polymers using these defined initiators.
  • TAPP for example, can afford initiation and low residual peroxide residue after polymerization; furthermore it is a low energy producing radical generator with reduced capacity to extract a proton from the PVP polymer. This fact enhances the stability of the PVP polymer. Even if it contains some initiator residue, it will pass the tests used to determine tablet stability, e.g. accelerated ageing-dissolution testing.
  • the t-amylperoxy pivalate initiator for example, can be employed in the polymerization of vinylpyrrolidone in an amount of about 0.01 to 10% by wt. of the monomers, preferably about 0.1 to 5%.
  • the PVP polymers thus-produced are characterized by substantially water soluble (more linear, less
  • the t-amylperoxy pivalate may be obtained from the Pennwalt Corp. under their trade name of Lupersol 554M75, which is sold as a 75% by weight active solution in
  • Suitable azo-type initiators for use herein include 2,2'-azobis(isobutyronitrile), often referred to as AIBN, which is sold by Dupont under the tradename Vazo 64; 2,2'-azobis(2-methylbutanenitrile), which is Vazo 67;
  • ABVN 2,2'-azobis(2,4-dimethylpentanenitrile, often referred to as ABVN, which is Vazo 52;
  • azo-type initiators generate highly selective tertiary alkyl radicals which have a reduced propensity to attack the backbone of the polymer. This effect reduces chain branching and crosslinking and should free radicals be generated in subsequent polymer storage (even after the post polymerization heating step designed to assure very low levels of residual initiator) prevents the possibility of further reactions such as crosslinking.
  • Redox initiators i.e., systems based on mixtures of
  • Free-radical polymerizastion is used in redox mechanisms, as for example, in the system ferrous ion plus hydrogen peroxide (Fenton's reagent), since it provides an intervention of free radicals and allows their rate of formation to be measured.
  • Feton's reagent ferrous ion plus hydrogen peroxide
  • Many redox initiators are known and numerous "recipes" are current in polymerization technology. Redox initiators for use herein are classified according to their solubilities (in water or organic liquids) or their mode of radical generation.
  • transition metal ions such as Ti 3+ can enter into similar reactions.
  • hydroperoxides are well-known components of redox systems and their reduction by ferrous salts has been investigated in detail.
  • the primary step is the one-electron transfer and bond cleavage process.
  • the product is an alkyloxy rather than a hydroxyl radical.
  • hydroperoxides are cumene, p-menthane, and p-isopropylcumene. It is common practice to add a second reducing agent such as glucose, fructose, dihydroxyacetone, or sodium formaldehyde sulfoxylate to reduce the ferric ion formed to ferrous and so keep up the rate of initiation.
  • a second reducing agent such as glucose, fructose, dihydroxyacetone, or sodium formaldehyde sulfoxylate to reduce the ferric ion formed to ferrous and so keep up the rate of initiation.
  • Strongly reducing metal ions may enter into redox processes with compounds other than peroxide; for example, Ti 3+ can reduce hydroxylamine in acid solution to NH 2 radicals.
  • Other metal ions (Cr 2+ , V 2+ , Fe 2+ ) behave similarly. These combinations are capable of initiating VP polymerization.
  • themetal ion is the reducing component; however, many strongly oxidizing metal ions participate in single-electron
  • Typical oxidizing agents are potassium persulfate,
  • Reducing agents include sodium hyposulfite, sodium metabisulfite, sodium sulfide, sodium thiosulfate, and hydrazine hydrate. No transition metal derivatives are included in these examples. Both oxidizing and reducing components form free radicals, which, in principle, may initiate polymerization, although the behavior in any given system depends on the radical and monomer reactivities.
  • Organic peroxides may react in nonaqueous solution by redox processes. It has long been known that benzoyl peroxide can enter into relatively rapid reactions with primary, secondary, and tertiary amines.
  • dimethylaniline are typical.
  • the reactants form a complex which cleaves into radicals.
  • a reducing agent must be present to regenerate the ferrous ion.
  • examples would be sodium hyposulfite, sodium metabisulfite, sodium sulfide and sodium thiosulfate. Numerous recipes are avilable and are known to those skilled in the art.
  • Redox systems capable of free radical initiation can also be generated by the reaction of dibenzoyl
  • dialkyl peroxides and organic reducing agents such as those containing sulfinic acids, alpha-ketols, formic acid, thiols and hydrazines.
  • FIGS. 1 and 2 are graphs representing dissolution rates, in percent drug released vs. time, from a
  • FIG. 3 is a graph representing compressibility, expressed in hardness (kp) vs. force (kg), for a
  • FIG. 4 is a graph representing friability, in percent vs. force (kg) for a pharmaceutical tablet
  • a pharmaceutical tablet is provided herein which has an enhanced drug dissolution rate and consists
  • the PVP of the present invention has a viscosity average molecular weight of at least one million, a weight average molecular weight of at least two million, and a relative viscosity of at least 1.2, most preferably about 1.2-1.5.
  • the tablet contains a suitable filler and/or
  • the pharmaceutical tablet consists essentially of, by weight, about 10-25% of poorly water-soluble drug, about 2-10% of PVP K-116-140, about 0.5-2% of a lubricant and about 65-85% of a filler, and is made by compression using wet granulation.
  • Pharmaceutical tablets were prepared by direct compression (A) or using wet granulation followed by compression (B).
  • magnesium stearate All ingredients, except magnesium stearate, were blended in a twin-shell blender for 12 minutes. Magnesium stearate then was added and blended for an additional three minutes. The mixture was then compressed on a Stokes B-2 rotary press to produce tablets of uniform weight (450 mg) and hardness of 8-10 KP.
  • Granulating Solution - In each formulation the binder consisted of PVP K-140 or PVP K-120 or PVP K-90 (50 g.) or Plasdone K-29/32 (100 g.) dissolved in purified water (450 g. for PVP K-90 or Plasdone K-120 and 300 g. for PVP K-29/32). The mixing time was 30 minutes for all binder solutions.
  • granulating solution was added slowly and mixed for 5 minutes at a speed number 1. To ensure even and complete granulation, the mixing blades and the bowl were scraped well with a spatula before allowing the granulation to mix for another 10 minutes at speed #2 (total mixing time - 15 minutes). The granulation end point was reached when the moistened powder mass had a "snowball" consistency and no dry powder was detected in the bowl. The sides of the mixer bowl could be easily cleaned by the movement of the formed granules.
  • the wet milling step was accomplished by passing the granulation through a Newark #30 screen by hand. The milled batch was placed on paper-lined trays and introduced into an over set at 40°C. for about 4 hours.
  • the dried granules were passed through a 12-mesh screen using an oscillator (Erweka AR 400).
  • Lubrication was performed by mixing magnesium stearate (0.5% of the weight of the milled batch to be tableted) for 3 minutes in a twin-shell v.
  • Tableting The tablets were compressed on a rotary tablet-press (Stokes B-2) to a targeted mass of 200 mg. The compressed force was also monitored during the tableting operation utilizing an oscillascope.
  • Dissolution - This test was performed on tablets stored for more than 12 hours after compression, using USP dissolution apparatus 2 (Vanderkamp 6000) with a paddle rotational speed of 100 rpm. Aqueous 0.1 N-HCl was utilized as the dissolution medium (900 ml). The amount of sulfathiazole or hydrochlorothiazide released in the medium as a function of time was determined using a UV photoelectron emission spectrometics
  • Hardness - The tablet hardness was determined 24 hours after compression using a Model HT-300 (Key
  • Friability - 10 tablets were weighed and placed in a friabilation apparatus and rotated on a wheel for 4 minutes at 25 rpm. Then the tablets were placed on a screen to allow any powder to pass through. The 10 tablets were reweighed. The results are expressed as follows:
  • Friability (Initial weight) - (Final Weight) X 100
  • FIGURE 1 AND 2.
  • the T-60 time to release 60% of the drug - See Table 1) for sulfathiazole and
  • hydrochlorothiazide with Plasdone ® K-120 is faster than with no Plasdone ® (sulfathiazole - > 3.75 times;
  • FIGURE 3 Plasdone ® K-120 when compressed at 1500 kg. yielded tablets with 8-10 kp whereas Plasdone ® K-29/32 and K-90 each required at least 2000 kg to yield tablets with the same hardness.
  • FIGURE 4 Friability results for tablets containing Plasdone ® K-120 at 1500 kg force were 0.9%
  • a 2-liter reactor provided with agitation, gas inlet, condenser, and thermocouple was charged with 270 g. (2.3 moles) of non-stabilized vinylpyrrolidone monomer, which was buffered with a solution of 0.27 g. of
  • tetrasodium pyrophosphate in 1,080 g. of deionized water.
  • the reactor was swept clean of oxygen by admitting nitrogen gas through the inlet tube.
  • the reactor was heated to 55°C. and 0.25 g. of t-amylperoxy pivalate (TAPP) was added ( ⁇ 0.1% by wt. of vinylpyrrolidone).
  • TAPP t-amylperoxy pivalate
  • the mixture was heated at 56°-59°C. for 5 hours, whereupon an additional 0.25 g. of TAPP was added and the reaction continued for 2 hours.
  • the mixture was heated to 85°C. and held at this temperature until the residual peroxide level was less than 500 ppm.
  • the product included 21% solids; the residual monomer content was
  • the PVP polymer product in water thus-obtained was characterized by being substantially linear, a K-value of 90, low residual initiator level, and excellent water dissolution.
  • thermocople was charged with 3,326 g. of deionized water, 1.6 g. of NH 4 OH (38% NH 3 ) and 2-5 ppm EDTA. Then was added 1,000 g. of unstabilized vinyl pyrrolidone, the mixture sparged with N 2 and heated to 55°C.
  • the temperature of the reactor was then maintained at 55°C. for 3 hours after which the system was heated to 80°C. in one-half hour and maintained at 80°C. for another 15 minutes.
  • the reactor was then cooled to room temperature and the product discharged.
  • the product had the following properties.
  • Example 4 The procedure of Example 4 was followed using 2,2'-azobis(isobutyronitrile) as the initiator with similar results.
  • Example 4 The procedure of Example 4 is followed using hydrogen peroxide-potassium persulfate redox catalyst with similar results.
  • Example 4 The procedure of Example 4 was followed using t-butylperoxy benzoate.
  • the PVP polymer obtained (K-90) had a relatively poorer water dissolution than the PVP polymer of Example 4.
  • acetaminophen as the active ingredient and 1% and 2% by weight of the PVP powder prepared as in Example 4.
  • the tablet was immersed in water and the amount of tablet dissolved with time was determined.
  • Example 10 The comparative experiments of Example 10 were repeated using hydrochlorothiazide as the active
  • chloropromazine methyl paraben, sulfothiazole,
  • trimethoprine and various non-sterioidal anti-inflammatory drugs as the active pharmaceutical ingredients at 1 and 2% levels in place of acetaminophen in Examples 10A and 10B. Similar differences in dissolution rates were obtained.

Abstract

Comprimé pharmaceutique ayant une vitesse de dissolution rapide. Le comprimé contient un ingrédient pharmaceutiquement actif et comme agent liant du PVP (polyvinyle-pyrrolidone) K-30 à K-120 linéaire, de préférence supérieur à 116, c'est-à-dire non réticulé. Le PVP utilisé dans l'invention est de préférence produit selon un procédé de polymérisation dans lequel le monomère de pyrrolidone vinylique est polymérisé en présence d'une amorce produisant une polymérisation de PVP linéaire, ainsi qu'un niveau d'amorce résiduel inférieur à 500 ppm.
PCT/US1992/009821 1991-11-15 1992-11-10 Comprime pharmaceutique a pvp ayant une vitesse de dissolution de medicament amelioree WO1993009763A1 (fr)

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US79256291A 1991-11-15 1991-11-15
US792,562 1991-11-15
US796,999 1991-11-25
US07/796,999 US5262171A (en) 1991-11-25 1991-11-25 Pharmaceutical tablet with PVP having enhanced drug dissolution rate

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Cited By (20)

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Publication number Priority date Publication date Assignee Title
FR2781672A1 (fr) * 1998-07-30 2000-02-04 Zambon Spa Compositions a dissolution rapide ayant une activite analgesique et comprimes obtenus a partir de celles-ci
US6761905B2 (en) 2001-05-01 2004-07-13 Wei Ming Pharmaceutical Mfg. Co., Ltd. Process for the preparation of direct tabletting formulations and aids
EP1666026B2 (fr) † 1999-02-08 2015-02-25 Intarcia Therapeutics, Inc Excipients visqueux à phase unique non aqueux stables et formulations utilisant ces excipients
US8992961B2 (en) 1999-02-08 2015-03-31 Intarcia Therapeutics, Inc. Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
US9526763B2 (en) 2005-02-03 2016-12-27 Intarcia Therapeutics Inc. Solvent/polymer solutions as suspension vehicles
US9539200B2 (en) 2005-02-03 2017-01-10 Intarcia Therapeutics Inc. Two-piece, internal-channel osmotic delivery system flow modulator
US9572889B2 (en) 2008-02-13 2017-02-21 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US9682127B2 (en) 2005-02-03 2017-06-20 Intarcia Therapeutics, Inc. Osmotic delivery device comprising an insulinotropic peptide and uses thereof
US9724293B2 (en) 2003-11-17 2017-08-08 Intarcia Therapeutics, Inc. Methods of manufacturing viscous liquid pharmaceutical formulations
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
USD835783S1 (en) 2016-06-02 2018-12-11 Intarcia Therapeutics, Inc. Implant placement guide
US10159714B2 (en) 2011-02-16 2018-12-25 Intarcia Therapeutics, Inc. Compositions, devices and methods of use thereof for the treatment of cancers
US10231923B2 (en) 2009-09-28 2019-03-19 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
US10501517B2 (en) 2016-05-16 2019-12-10 Intarcia Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US10527170B2 (en) 2006-08-09 2020-01-07 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies for use therein
US10835580B2 (en) 2017-01-03 2020-11-17 Intarcia Therapeutics, Inc. Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug
US10925639B2 (en) 2015-06-03 2021-02-23 Intarcia Therapeutics, Inc. Implant placement and removal systems
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
US11304961B2 (en) * 2017-12-18 2022-04-19 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone

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US4344934A (en) * 1978-11-20 1982-08-17 American Home Products Corporation Therapeutic compositions with enhanced bioavailability
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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2781672A1 (fr) * 1998-07-30 2000-02-04 Zambon Spa Compositions a dissolution rapide ayant une activite analgesique et comprimes obtenus a partir de celles-ci
WO2000006125A1 (fr) * 1998-07-30 2000-02-10 Zambon Group S.P.A. Compositions analgesiques a dissolution rapide contenant de l'ibuprofene
GR990100254A (el) * 1998-07-30 2000-02-29 Zambon Group S.P.A. Ταχεως διαλυομενες συνθεσεις εχουσες αναλγητικη δραση
BE1012510A3 (fr) * 1998-07-30 2000-11-07 Zambon Spa Compositions a dissolution rapide ayant une activite analgesique et comprimes obtenus a partir de celles-ci.
US6197336B1 (en) 1998-07-30 2001-03-06 Zambon Group S.P.A. Fast dissolving compositions having analgesic activity
EP1666026B2 (fr) † 1999-02-08 2015-02-25 Intarcia Therapeutics, Inc Excipients visqueux à phase unique non aqueux stables et formulations utilisant ces excipients
US8992961B2 (en) 1999-02-08 2015-03-31 Intarcia Therapeutics, Inc. Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
US6761905B2 (en) 2001-05-01 2004-07-13 Wei Ming Pharmaceutical Mfg. Co., Ltd. Process for the preparation of direct tabletting formulations and aids
US9724293B2 (en) 2003-11-17 2017-08-08 Intarcia Therapeutics, Inc. Methods of manufacturing viscous liquid pharmaceutical formulations
US9682127B2 (en) 2005-02-03 2017-06-20 Intarcia Therapeutics, Inc. Osmotic delivery device comprising an insulinotropic peptide and uses thereof
US9539200B2 (en) 2005-02-03 2017-01-10 Intarcia Therapeutics Inc. Two-piece, internal-channel osmotic delivery system flow modulator
US9526763B2 (en) 2005-02-03 2016-12-27 Intarcia Therapeutics Inc. Solvent/polymer solutions as suspension vehicles
US10363287B2 (en) 2005-02-03 2019-07-30 Intarcia Therapeutics, Inc. Method of manufacturing an osmotic delivery device
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
US10527170B2 (en) 2006-08-09 2020-01-07 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies for use therein
US10441528B2 (en) 2008-02-13 2019-10-15 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US9572889B2 (en) 2008-02-13 2017-02-21 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US10869830B2 (en) 2009-09-28 2020-12-22 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
US10231923B2 (en) 2009-09-28 2019-03-19 Intarcia Therapeutics, Inc. Rapid establishment and/or termination of substantial steady-state drug delivery
US10159714B2 (en) 2011-02-16 2018-12-25 Intarcia Therapeutics, Inc. Compositions, devices and methods of use thereof for the treatment of cancers
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
US10583080B2 (en) 2014-09-30 2020-03-10 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
US10925639B2 (en) 2015-06-03 2021-02-23 Intarcia Therapeutics, Inc. Implant placement and removal systems
US10501517B2 (en) 2016-05-16 2019-12-10 Intarcia Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US11840559B2 (en) 2016-05-16 2023-12-12 I2O Therapeutics, Inc. Glucagon-receptor selective polypeptides and methods of use thereof
US11214607B2 (en) 2016-05-16 2022-01-04 Intarcia Therapeutics Inc. Glucagon-receptor selective polypeptides and methods of use thereof
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD912249S1 (en) 2016-06-02 2021-03-02 Intarcia Therapeutics, Inc. Implant removal tool
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
USD962433S1 (en) 2016-06-02 2022-08-30 Intarcia Therapeutics, Inc. Implant placement guide
USD835783S1 (en) 2016-06-02 2018-12-11 Intarcia Therapeutics, Inc. Implant placement guide
US10835580B2 (en) 2017-01-03 2020-11-17 Intarcia Therapeutics, Inc. Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug
US11654183B2 (en) 2017-01-03 2023-05-23 Intarcia Therapeutics, Inc. Methods comprising continuous administration of exenatide and co-administration of a drug
US11304961B2 (en) * 2017-12-18 2022-04-19 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone

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