WO1999049849A1 - Liposomal bupivacaine compositions and methods of preparation - Google Patents
Liposomal bupivacaine compositions and methods of preparation Download PDFInfo
- Publication number
- WO1999049849A1 WO1999049849A1 PCT/US1999/006958 US9906958W WO9949849A1 WO 1999049849 A1 WO1999049849 A1 WO 1999049849A1 US 9906958 W US9906958 W US 9906958W WO 9949849 A1 WO9949849 A1 WO 9949849A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- liposomes
- drug
- liposomal
- local anesthetic
- bup
- Prior art date
Links
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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
Definitions
- the present invention is directed to liposomal compositions of local anesthetics, such as bupivacaine, and in particular to DRV (dehydration-rehydration vesicle) compositions and methods of their preparation and use.
- local anesthetics such as bupivacaine
- DRV dehydration-rehydration vesicle
- liposomal local anesthetics can be used to manage acute pain in-patients.
- Critical requirements for a liposomal formulation include reliability and reproducibility in manufacturing and performance, and adequate shelf stability to permit long term storage.
- Liposomal local anesthetic compositions which have been described in the literature, employ multilamellar vesicles (MLV) and large unilamellar vesicles (LUV). These liposomes are stored in aqueous media, whereby the components lipids are subject to degradation due to oxidation and hydrolysis. Moreover, encapsulated drug may leak from the liposome into the aqueous medium.
- the invention provides a method of providing long term local anesthesia, comprising administering to a subject in need of such treatment a liposomal local anesthetic formulation prepared by the dehydration-rehydration method, in which lyophilized liposomes encapsulating the local anesthetic are rehydrated by agitating in an aqueous medium.
- the preparation includes the further step of washing the rehydrated liposomes in hyperosmotic saline solution.
- An exemplary local anesthetic is bupivacaine.
- lidocaine ropivacaine, levobupivacaine, procaine, chloroprocaine, benzocaine, etidocaine, mepivacaine, prilocaine, ciprocaine, tetracaine, dibucaine, heptacaine, mesocaine, propanocaine, carbisocaine, and butacaine.
- the invention provides a method of preparing a liposomal drug composition having a high drug/lipid ratio, comprising the steps of encapsulating the drug in liposomes, lyophilizing the liposomes, rehydrating the lyophilized liposomes by agitating in an aqueous medium, and washing the rehydrated liposomes in hyperosmotic saline solution.
- the drug is a local anesthetic, such as bupivacaine.
- the invention provides a liposomal local anesthetic composition having a high drug/lipid ratio, where the local anesthetic is preferably bupivacaine, and the drug/lipid ratio is preferably at least 0.3 (mole/mole), and more preferably at least 0.33 (mole/mole).
- Such liposomal local anesthetic compositions are prepared by encapsulating the local anesthetic in liposomes, lyophilizing the liposomes, and rehydrating the lyophilized liposomes by agitating in an aqueous medium, and washing the rehydrated liposomes in hyperosmotic saline solution.
- Figure 1 shows the duration of sensory block observed in mice after administration of 0.5 % free, 0.5 % liposomal (DRV), and 3.5% liposomal bupivacaine (BUP);
- Figure 2 shows the amount of bupivacaine remaining at the site of injection at a series of time intervals after administration of the compositions of Fig. 1 ;
- Figure 3 is a kinetic release profile of the free and liposomal bupivacaine formulations, showing the data of Figure 2 expressed as a percentage of initial dose.
- Bupivacaine hydrochloride (BUP) (Sigma, St. Louis, MO) was encapsulated into liposomes by the dehydration-rehydration (DRV) technique, as described, for example, in Kirby et al.
- DUVs dehydration-rehydration
- Dehydrated-rehydrated vesicles are liposomes which can be reproducibly prepared, stored in a lyophilized state, and rehydrated immediately prior to administration (Kirby). Maintaining the formulations in the dehydrated state greatly reduces the likelihood of degradation, and confers shelf stability (Zuidam).
- DMPC l,2-dimyristoyl-sn-glycero-3-phosphatidylcholine
- DSPC distearoyl-sn-glycero-3-phosphatidylcholine
- Tm (Tm) of 23°C, tends to give a more fluid membrane, while DSPC, having a Tm of 52.5°C, gives a more rigid membrane, as discussed further below.
- DMPC or DSPC and CHOL were co-dissolved in tert-butanol (Fisher, Pittsburgh, PA) and lyophilized.
- the dried lipid was hydrated with water at 60°C to form multilamellar vesicles (MLV).
- MLV multilamellar vesicles
- SUVs Small unilamellar vesicles
- SUV size was confirmed to be approximately 100 nm by photon correlation spectroscopy (N4 Plus, Coulter, Miami, FL).
- BUP was dissolved in the SUVs at pH 4.0 or 5.5. The solution was then divided, transferred to glass bottles, frozen and lyophilized overnight.
- the lyophilized powder was hydrated with saline while vortexing at 60° C to achieve a final lipid concentration of 10% .
- free drug was removed from the final liposomal formulations by 4 successive centrifugal washings with normal saline at 4°C, followed by a final wash with hyperosmotic saline (580 mM) at 4°C.
- hyperosmotic saline e.g. having a concentration of about 300 to 600 mM NaCI
- BUP concentration in the liposomes was determined by high performance liquid chromatography (HPLC). Isopropanol (1 : 1000) was used to dissolve washed liposomes, and aliquots were injected onto an 8-mm x 100-mm column (Radial-Pak 8NVCN, 4mm, Waters, Milford, MA). A mobile phase of acetonitrile: phosphate buffer, 25 mM, pH 4.0 (75:25) was used, and absorption was measured at a wavelength of 210 nm. The retention time of BUP was approximately 4.7 min. Phospholipid concentration was determined using procedures described in Bartlett or Stewart. The BUP to phospholipid ratio (BUP/PL) was then calculated.
- HPLC high performance liquid chromatography
- the size of the multilamellar DRV liposomes was determined by photon correlation spectroscopy spectroscopy (N4 Plus, Coulter, Miami, FL). The size distributions of all formulations were similar; the mean diameter of liposomes of formulation 3 was 1931 ⁇ 722 nm. All in vitro liposomal characterization procedures were performed in triplicate. Results are summarized in Table I.
- liposomes prepared with DSPC as the matrix lipid had higher BUP/PL ratios.
- the two BUP concentrations resulted in similar BUP/PL ratios.
- the pH of the solution did not affect final BUP/PL ratio, so all subsequent work was done at pH 5.5.
- Formulation 3 gave a drug/PC ratio of about 0.36, which is much higher than previously reported for MLV loaded by standard methods (e.g. about 0.1, reported by F. Legros et al), and even higher than reported for remote loading using sodium citrate (about 0.26).
- a high drug-to- lipid ratio is especially important in treatment of superficial wounds, where a high amount of lipid residue is undesirable.
- mice were injected with liposomal BUP compositions having 0.5 wt % and 3.5 wt % bupivacaine, respectively, formed by dilution (as necessary ) of formulation 3, above.
- Free BUP 0.5%), hyperosmotic saline (580 mM), or drug-free liposomes were used as controls.
- 150ml of test solution was injected subcutaneously using a #25g needle in 8 mice. After injection, sensory block was assessed at 5, 15, 30 minutes and then at 1 , 1.5, 2, 3, 4.5, 6, 9, 12, 14, 16, 17, and 19 hours. Failure to vocalize in response to stimulation with threshold current was taken as analgesia. Testing was continued until two successive tests resulted in vocalization (i.e., absence of analgesia). Duration of sensory block was determined using Kruskall Wallis, with p ⁇ 0.05 considered significant. Results are presented in Figure 1.
- mice receiving 0.5 % free BUP analgesia was exhibited at 30 minutes, but none was detected at 2 hours.
- mice given 0.5 % liposomal BUP all animals demonstrated analgesia at 3 hours, and it was not until 6 hours that analgesia was not detected.
- a 6 fold increase in analgesic duration was observed when a 0.5 % concentration of BUP was injected in liposomes, and this increased to a 28 fold increase when 3.5 % liposomal BUP was injected.
- the slow release of drug from the liposomes provides the benefits of 1) a prolonged residence of drug at the site of injection and 2) a decrease in systemic drug availability.
- a comparison of Figures 2 and 3 shows that much of the injected drug remained associated with the liposomal vehicles after analgesia was no longer exhibited. It is possible that the continued release of BUP produced a weak analgesic effect, which was not detected by our testing technique.
- Future DRV studies could be directed at decreasing the size of this drug reservoir and achieving more consistent release, perhaps by the use of smaller liposomes.
- the DRV liposomes in the current study were large, with a mean diameter approximately 2 mm. Although larger liposomes tend to remain longer at the site of injection; a smaller liposome size could result in more thorough release of BUP and less retention in the depot after the analgesic effect has subsided.
- the liposomal BUP formulations described herein significantly prolonged the duration of sensory block after subcutaneous administration, in comparison to free bupivacaine.
- the present liposomal formulations are distinguished in that they are formed by the DRV technique, thus giving long storage stability, preferably employ DSPC or another high Tm lipid, and have a high (i.e. greater than about 0.15, preferably greater than about 0.25, and more preferably greater than about 0.35) drug-to-lipid ratio.
- Preparation of the formulations employs a hyperosmotic saline wash, as described above, which results in a high concentration of drug in the final emulsion. Other local anesthetics may also be used in these formulations.
- a “local anesthetic”, as used herein, refers to a member of the "caine” family of local anesthetic compounds, having physicochemical properties similar to bupivacaine. Structural features common to these compounds include a benzene ring linked via an ester or amide linkage, or, less frequently, a carbamate linkage, to an aliphatic or alicyclic group containing a tertiary or quaternary amine. The length of the linkage, i.e. the distance between the benzene ring and the amine, is typically about 6-9 A.
- These compounds include, for example, lidocaine, ropivacaine, levobupivacaine, procaine, chloroprocaine, benzocaine, etidocaine, mepivacaine, prilocaine, ciprocaine, tetracaine, dibucaine, heptacaine, mesocaine, propanocaine, carbisocaine, and butacaine.
- compositions may be administered subcutaneously, intraperitoneally, topically, and into the neuraxis.
- Methods for preparing suitable dosage forms are known or will be apparent to 8 those skilled in the art; for example, see Remington 's Pharmaceutical Sciences (19th Ed., Williams & Wilkins, 1995).
- the composition to be administered will contain a quantity of bupivacaine in a pharmaceutically effective amount for effecting anesthesia in the subject.
- Such formulations may allow a single injection to provide prolonged analgesia, and thus obviate the need for repeated injections, catheterization, or use of an infusion pump, as are commonly required with conventional anesthetics. Administration could be performed during or at the end of surgery, and by providing effective pain release could obviate the need for parental narcotics.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Anesthesiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL13867299A IL138672A0 (en) | 1998-03-31 | 1999-03-30 | Liposomal bupivacaine compositions and methods of preparation |
CA002326348A CA2326348C (en) | 1998-03-31 | 1999-03-30 | Liposomal bupivacaine compositions and methods of preparation |
EP99915127A EP1071401A4 (en) | 1998-03-31 | 1999-03-30 | Liposomal bupivacaine compositions and methods of preparation |
AU33720/99A AU757686B2 (en) | 1998-03-31 | 1999-03-30 | Liposomal bupivacaine compositions and methods of preparation |
IL138672A IL138672A (en) | 1998-03-31 | 2000-09-24 | Liposomal anesthetic compositions, a method of preparation and uses thereof |
US10/620,006 US6926905B2 (en) | 1998-03-31 | 2003-07-16 | Liposomak compositions and methods of preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8019598P | 1998-03-31 | 1998-03-31 | |
US60/080,195 | 1998-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999049849A1 true WO1999049849A1 (en) | 1999-10-07 |
Family
ID=22155864
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/006958 WO1999049849A1 (en) | 1998-03-31 | 1999-03-30 | Liposomal bupivacaine compositions and methods of preparation |
Country Status (6)
Country | Link |
---|---|
US (1) | US6926905B2 (en) |
EP (1) | EP1071401A4 (en) |
AU (1) | AU757686B2 (en) |
CA (1) | CA2326348C (en) |
IL (2) | IL138672A0 (en) |
WO (1) | WO1999049849A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001019403A1 (en) * | 1999-09-14 | 2001-03-22 | Lim Jung Ok | Liposomal mixture of local anesthetics and manufacturing method thereof |
KR20010090030A (en) * | 2001-08-09 | 2001-10-18 | 임정옥 | Manufacturing and synergic effect of topical anesthetic formula consisted of mixed local anesthetics |
EP1189597A1 (en) * | 1999-06-04 | 2002-03-27 | SkyePharma Inc. | Oil-core compositions for the sustained release of hydrophobic drugs |
US9326953B2 (en) | 2003-04-25 | 2016-05-03 | The Penn State Research Foundation | Method and system for systemic delivery of growth arresting, lipid-derived bioactive compounds |
WO2020176568A1 (en) * | 2019-02-26 | 2020-09-03 | Tlc Biopharmaceuticals, Inc. | Pharmaceutical compositions for use in treating pain |
US11839685B2 (en) * | 2008-10-07 | 2023-12-12 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Composition of matter comprising liposomes embedded in a polymeric matrix and methods of using same |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2473719A1 (en) * | 2002-01-22 | 2003-07-31 | Wisconsin Alumni Research Foundation | Liposome-encapsulated opioid analgesics prepared by rehydration/dehydration method |
JP2007522085A (en) * | 2003-06-27 | 2007-08-09 | スミスクライン・ビーチャム・コーポレイション | Stabilized topotecan liposome compositions and methods |
US8753673B2 (en) * | 2006-05-23 | 2014-06-17 | Taiwan Liposome Co. Ltd. | Liposome composition for delivery of a therapeutic agent to eyes |
US9506103B2 (en) | 2010-05-28 | 2016-11-29 | Diagon Ltd. | Procedure for biphasic preparation of liposomes and application thereof in manufacturing diagnostic reagents |
ES2841143T3 (en) | 2014-02-18 | 2021-07-07 | Glenn Abrahmsohn | Compositions comprising bicarbonate and calcium salts for pain relief without numbness |
AU2018323436B2 (en) | 2017-08-28 | 2023-12-21 | Tlc Biopharmaceuticals, Inc. | Sustained-release anesthetic compositions and methods of preparation thereof |
EP3773504A1 (en) * | 2018-03-30 | 2021-02-17 | TLC Biopharmaceuticals, Inc. | Sustained-release anesthetic compositions and methods of preparation thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5244678A (en) * | 1986-01-14 | 1993-09-14 | Ire-Celltarg S.A. | Pharmaceutical composition containing a local anesthetic and/or centrally acting analgesic encapsulated in liposomes |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880635B1 (en) * | 1984-08-08 | 1996-07-02 | Liposome Company | Dehydrated liposomes |
ATE68968T1 (en) * | 1985-11-22 | 1991-11-15 | Takeda Chemical Industries Ltd | LIPOSOME COMPOSITION. |
CH672733A5 (en) * | 1987-05-22 | 1989-12-29 | Bracco Ind Chimica Spa | |
US5244878A (en) * | 1987-12-30 | 1993-09-14 | Institut Francais Du Petrole | Process for delaying the formation and/or reducing the agglomeration tendency of hydrates |
GB9609779D0 (en) * | 1996-05-10 | 1996-07-17 | Univ Bruxelles | Freeze dried liposome encapsulated amphiphilic drug compositions and a process for the preparation thereof |
-
1999
- 1999-03-30 CA CA002326348A patent/CA2326348C/en not_active Expired - Fee Related
- 1999-03-30 WO PCT/US1999/006958 patent/WO1999049849A1/en active IP Right Grant
- 1999-03-30 EP EP99915127A patent/EP1071401A4/en not_active Withdrawn
- 1999-03-30 AU AU33720/99A patent/AU757686B2/en not_active Ceased
- 1999-03-30 IL IL13867299A patent/IL138672A0/en active IP Right Grant
-
2000
- 2000-09-24 IL IL138672A patent/IL138672A/en not_active IP Right Cessation
-
2003
- 2003-07-16 US US10/620,006 patent/US6926905B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5244678A (en) * | 1986-01-14 | 1993-09-14 | Ire-Celltarg S.A. | Pharmaceutical composition containing a local anesthetic and/or centrally acting analgesic encapsulated in liposomes |
Non-Patent Citations (2)
Title |
---|
KIRBY C, GREGORIADIS G: "DEHYDRATION-REHYDRATION VESICLES: A SIMPLE METHOD FOR HIGH YIELD DRUG ENTRAPMENT IN LIPOSOMES", BIOTECHNOLOGY., BUTTERWORTHS, LONDON., GB, 1 November 1984 (1984-11-01), GB, pages 979 - 984, XP002919104, ISSN: 0740-7378 * |
See also references of EP1071401A4 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1189597A1 (en) * | 1999-06-04 | 2002-03-27 | SkyePharma Inc. | Oil-core compositions for the sustained release of hydrophobic drugs |
EP1189597A4 (en) * | 1999-06-04 | 2008-06-18 | Pacira Pharmaceuticals Inc | Oil-core compositions for the sustained release of hydrophobic drugs |
WO2001019403A1 (en) * | 1999-09-14 | 2001-03-22 | Lim Jung Ok | Liposomal mixture of local anesthetics and manufacturing method thereof |
KR20010090030A (en) * | 2001-08-09 | 2001-10-18 | 임정옥 | Manufacturing and synergic effect of topical anesthetic formula consisted of mixed local anesthetics |
US9326953B2 (en) | 2003-04-25 | 2016-05-03 | The Penn State Research Foundation | Method and system for systemic delivery of growth arresting, lipid-derived bioactive compounds |
US11839685B2 (en) * | 2008-10-07 | 2023-12-12 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Composition of matter comprising liposomes embedded in a polymeric matrix and methods of using same |
WO2020176568A1 (en) * | 2019-02-26 | 2020-09-03 | Tlc Biopharmaceuticals, Inc. | Pharmaceutical compositions for use in treating pain |
Also Published As
Publication number | Publication date |
---|---|
AU3372099A (en) | 1999-10-18 |
US20040018230A1 (en) | 2004-01-29 |
EP1071401A4 (en) | 2002-05-15 |
IL138672A0 (en) | 2001-10-31 |
CA2326348A1 (en) | 1999-10-07 |
CA2326348C (en) | 2009-10-06 |
IL138672A (en) | 2006-07-05 |
AU757686B2 (en) | 2003-03-06 |
EP1071401A1 (en) | 2001-01-31 |
US6926905B2 (en) | 2005-08-09 |
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