U.S. patent application number 09/887039 was filed with the patent office on 2001-12-13 for medical emulsion for lubrication and delivery of drugs.
This patent application is currently assigned to SCIMED Life Systems, Inc.. Invention is credited to Bluni, Scott T., Dillard, David H., Fieggen, Bruce, Lyons, Robert T., Rauker, Robert M..
Application Number | 20010051595 09/887039 |
Document ID | / |
Family ID | 24128542 |
Filed Date | 2001-12-13 |
United States Patent
Application |
20010051595 |
Kind Code |
A1 |
Lyons, Robert T. ; et
al. |
December 13, 2001 |
Medical emulsion for lubrication and delivery of drugs
Abstract
A medical lubricant suitable for injection into the blood stream
of a patient. The lubricant is suitable for use with rotating
equipment such as atherectomy drive shafts moving within sheaths
and over guide wires and other minimally invasive medical devices
introduced into a patient through a catheter like instrument. The
lubricant is an oil-in-water emulsion including a surfactant, a
co-surfactant, and a pH buffer. The lubricant can further include a
cryogenic agent and a pH adjusting agent. One lubricant includes
olive oil as an emulsified oil, egg yolk phospholipid as a
surfactant, sodium deoxycholate as a co-surfactant, glycerin as a
cryogenic agent, L-histidine as a pH buffer, and is pH adjusted
using sodium hydroxide. The lubricant can also include a
therapeutic agent. The lubricant can withstand freeze/thaw cycles
as well as saline dilution, heating, and shear stress without
significant creaming, separation, or unacceptable increases in oil
droplet size. Compared to saline, the lubricant provides
significantly increased lubrication efficiency for rapidly moving
parts.
Inventors: |
Lyons, Robert T.; (Laguna
Hills, CA) ; Dillard, David H.; (Redmond, WA)
; Fieggen, Bruce; (Wayne, NJ) ; Rauker, Robert
M.; (Ashland, MA) ; Bluni, Scott T.; (Sudbury,
MA) |
Correspondence
Address: |
CHRISTENSEN, O'CONNOR, JOHNSON, KINDNESS, PLLC
1420 FIFTH AVENUE
SUITE 2800
SEATTLE
WA
98101-2347
US
|
Assignee: |
SCIMED Life Systems, Inc.
|
Family ID: |
24128542 |
Appl. No.: |
09/887039 |
Filed: |
June 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09887039 |
Jun 21, 2001 |
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09534056 |
Mar 24, 2000 |
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6281175 |
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09534056 |
Mar 24, 2000 |
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08935698 |
Sep 23, 1997 |
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6054421 |
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Current U.S.
Class: |
508/491 ;
508/427; 508/428; 508/513; 514/937; 514/938 |
Current CPC
Class: |
Y10S 514/937 20130101;
Y10S 514/938 20130101; A61B 17/320758 20130101; A61P 23/00
20180101; A61K 9/0019 20130101; A61P 3/06 20180101; A61P 9/10
20180101; A61K 9/1075 20130101; A61P 7/02 20180101; A61P 35/00
20180101; A61P 29/00 20180101; B82Y 5/00 20130101 |
Class at
Publication: |
508/491 ;
508/427; 508/428; 508/513; 514/937; 514/938 |
International
Class: |
C10M 173/00; A61K
009/107 |
Claims
What is claimed is:
1. A medical lubricant oil emulsion comprising a mixture of: an
oil; a surfactant; a co-surfactant; a pH buffer; wherein when said
pH buffer is an amino acid buffer and said amino acid buffer has a
concentration of less than 0.20 g/100 mL emulsion; and water.
2. A medical lubricant as recited in claim 1, wherein said oil
comprises at least 60% mixed triglycerides of mono-unsaturated
oleic acid, said surfactant is a phospholipid, said co-surfactant
is a bile salt, and said pH buffer is an amino acid buffer having a
concentration of less than 0.20 g/100 mL emulsion.
3. A medical lubricant as recited in recited in claim 2, wherein
said oil is a vegetable oil.
4. A medical lubricant as recited in claim 3, wherein said
vegetable oil is selected from the group of refined oils consisting
of almond oil, coconut oil, corn oil, cotton seed oil, marine oil,
olive oil, palm kernel oil, peanut oil, safflower oil, sesame oil,
soybean oil, sunflower oil, and physical or interesterified
mixtures thereof.
5. A medical lubricant as recited in recited in claim 4, wherein
said vegetable oil is purified olive oil comprised of at least 60%
mixed triglycerides of mono-unsaturated oleic acid.
6. A medical lubricant as recited in claim 2, wherein said
phospholipid is selected from the group consisting of soy bean and
egg yolk phospholipids.
7. A medical lubricant as recited in claim 2, wherein said
phospholipid is egg yolk phospholipid.
8. A medical lubricant as recited in claim 2, wherein said bile
salt is selected from the group of salts of bile acids consisting
of cholic acid, deoxycholic acid, glycocholic acid, taurocholic
acid, and mixtures thereof.
9. A medical lubricant as recited in claim 8, wherein said bile
salt is sodium deoxycholate.
10. A medical lubricant as recited in claim 2, wherein said amino
acid buffer is selected from the group consisting of alanine,
aspartic acid, glycine, histidine, isoleucine, leucine, methionine,
phenylalanine, proline, serine, valine, and mixtures thereof.
11. A medical lubricant as recited in claim 10, wherein said amino
acid buffer is L-histidine.
12. A medical lubricant as recited in claim 2, further comprising a
cryogenic agent.
13. A medical lubricant as recited in claim 12, wherein said
cryogenic agent is glycerin.
14. A medical lubricant as recited in claim 2, further comprising a
heavy metal chelator.
15. A medical lubricant as recited in claim 14, wherein said
chelator includes a physiologically acceptable salt of
ethylenediamine tetracetic acid (EDTA).
16. A medical lubricant oil emulsion comprising: an oil; a
phospholipid; a bile salt, a cryogenic agent; an amino acid buffer
having a concentration of less than 0.20 g/100 mL emulsion; and
water.
17. A medical lubricant as recited in claim 16, wherein said lipid
emulsion has a mean droplet size less than about 5 micro
meters.
18. A medical lubricant as recited in claim 16, wherein said lipid
emulsion has a mean droplet size less than about 1 micrometer.
19. A medical lubricant as recited in claim 16, wherein said oil
has a concentration of between about 5 and about 40 g/100 mL
emulsion, said phospholipid includes egg yolk phospholipid and has
a concentration of between about 0.3 and about 3 g/100 mL emulsion,
said bile salt has a concentration of between about 0.04 and about
4.0 g/100 mL emulsion, said cryogenic agent is selected from the
group consisting of refined propylene glycol and glycerin and has a
concentration between about 1 and about 30 g/100 mL emulsion, and
said amino acid buffer has a concentration of between about 0.01
and about 0.19 g/100 mL emulsion.
20. A medical lubricant as recited in claim 19, wherein said oil
includes olive oil and has a concentration of between about 15 and
about 25 g/100 mL emulsion, said phospholipid has a concentration
of between about 0.6 and about 1.8 g/100 mL emulsion, said bile
salt includes sodium deoxycholate and has a concentration of
between about 0.2 and about 0.8 g/100 mL emulsion, said cryogenic
agent includes glycerin and has a concentration between about 2 and
about 20 g/100 mL emulsion, and said amino acid buffer includes
L-histidine and has a concentration of between about 0.05 and 0.19
g/100 mL emulsion.
21. A medical lubricant oil emulsion comprising: refined olive oil;
egg yolk phospholipid; sodium deoxycholate; glycerin; L-histidine
having a concentration of less than 0.20 g/mL emulsion; and water
for injection.
22. A medical lubricant as recited in claim 21, further comprising
disodium EDTA and sodium hydroxide.
23. A medical lubricant oil emulsion comprising a mixture of: an
oil; a surfactant; a co-surfactant; a pH buffer; a therapeutic
agent; and water.
24. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one anti-thrombogenic agent
chosen from heparin, heparin derivatives, urokinase and
dextro-phenylalanine-proline-arginine chloromethylketone.
25. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one anti-proliferative agent
chosen from enoxaprin, angiopeptin, a monoclonal antibody capable
of blocking smooth muscle cell proliferation, hirudin, and
acetylsalicylic acid.
26. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one anti-inflammatory agent
chosen from dexamethasone, prednisolone, corticosterone,
budesonide, estrogen, sulfasalazine, and mesalamine.
27. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one
antineoplastic/antiproliferative/anti-mitoti- c agent chosen from
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, and thymidine kinase
inhibitors.
28. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one anesthetic agents chosen
from lidocaine, bupivacaine, and ropivacaine.
29. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one anti-coagulant chosen from
dextro-phenylalanine-proline-arginine chloromethylketone, an
arginine-glycine-aspartic acid peptide-containing compound,
heparin, antithrombin compounds, platelet receptor antagonists,
anti-thrombin antibodies, anti-platelet receptor antibodies,
aspirin, prostaglandin inhibitors, platelet inhibitors, and tick
antiplatelet peptides.
30. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one vascular cell growth
promoter chosen from growth factor inhibitors, growth factor
receptor antagonists, transcriptional activators of genes encoding
vascular cell growth promoter proteins, and translational
activators of mRNAs encoding vascular cell growth promoter
proteins.
31. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one vascular cell growth
inhibitor chosen from growth factor inhibitors, growth factor
receptor antagonists, transcriptional repressors of genes encoding
vascular cell growth inhibitors, translational repressors of mRNAs
encoding vascular cell growth inhibitors, DNA replication
inhibitors, vascular cell growth inhibitory antibodies, antibodies
directed against growth factors, bifunctional molecules consisting
of a growth factor and a cytotoxin, and bifunctional molecules
consisting of an antibody, and a cytotoxin.
32. A medical lubricant as recited in claim 23, wherein said
therapeutic agent is selected from the group consisting of
cholesterol-lowering agents, vasodilating agents, and agents which
interfere with endogenous vascoactive mechanisms.
33. A medical lubricant as recited in claim 23, wherein said
therapeutic agent comprises at least one agent chosen from a
substantially purified genetic material, a substantially purified
protein, and cells.
34. A medical lubricant as recited in claim 33, wherein said
genetic material comprises at least one polynucleotide chosen from
anti-sense DNA, anti-sense RNA, DNA coding for an anti-sense RNA,
DNA coding for a tRNA, DNA coding for a rRNA, and DNA coding for a
protein.
35. A medical lubricant as recited in claim 33, wherein said cells
are human cells that are of autologous or allogeneic origin.
36. A medical lubricant as recited in claim 33, wherein said cells
are xenogeneic non-human cells.
37. A medical lubricant as recited in claim 33, wherein said
therapeutic agent comprises at least one protein chosen from acidic
fibroblast growth factors, basic fibroblast growth factors,
vascular endothelial growth factor, epidermal growth factor,
transforming growth factor .alpha. and .beta., platelet-derived
endothelial growth factor, platelet-derived growth factor, tumor
necrosis factor .alpha., hepatocyte growth factor, insulin like
growth factor, and bone morphogenic proteins.
38. A medical lubricant as recited in claim 33, wherein said
genetic material comprises at least one DNA encoding a protein
chosen from acidic fibroblast growth factors, basic fibroblast
growth factors, vascular endothelial growth factor, epidermal
growth factor, transforming growth factor .alpha. and .beta.,
platelet-derived endothelial growth factor, platelet-derived growth
factor, tumor necrosis factor .alpha., hepatocyte growth factor,
insulin like growth factor, and bone morphogenic proteins.
39. A method of lubricating an intravascular device comprising:
preparing a patient for a medical procedure; inserting into the
patient a medical device in need of lubrication; infusing a medical
lubricant into the patient during said insertion or during
operation of said medical device, said medical lubricant oil
emulsion comprising: olive oil; an egg yolk phospholipid; a bile
salt; an amino acid buffer; a therapeutic agent; and water.
40. A method according to claim 39 wherein the medical procedure is
atherectomy, the medical device is an intravascular device, capable
of differentially removing intravascular deposits from the walls of
an artery; and the therapeutic agent comprises a cell proliferation
inhibitor that provides an anti-restenosis effect.
41. A method according to claim 39 wherein the medical procedure is
myocardial revascularization, the medical device is a myocardial
revascularization device, and the therapeutic agent comprises an
agent that promotes angiogenesis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/534,056, filed Mar. 24, 2000, which is a
Continuation-in-Part of U.S. patent application Ser. No.
08/935,698, filed Sep. 23, 1997, now U.S. Pat. No. 6,054,421, the
benefit of the filing dates being claimed under 35 U.S.C. .sctn.
120.
FIELD OF THE INVENTION
[0002] This invention relates to a lubricating composition for use
with biomedical devices. More particularly, this invention relates
to an injectable emulsion capable of being used within human
arteries during a rotational atherectomy procedure that both
lubricates the atherectomy device and is capable of acting as a
drug carrier.
BACKGROUND OF THE INVENTION
[0003] It is well known that, for various reasons, humans can
develop a condition in which a type of plaque or hard deposit
builds up along the walls of the blood vessels, thereby partially
blocking the blood flow and causing severe medical conditions.
Several different procedures have been developed for dealing with
this situation. One such procedure is rotational atherectomy, in
which a rotary mechanical system removes relatively hard
intravascular deposits from the walls of human arteries by
differentially cutting away the inelastic, hardened deposits while
sparing the soft, elastic tissue of the inner lining of the human
blood vessels. The seminal patent that discloses a device for
performing this procedure is U.S. Pat. No. 4,990,134 (Auth)
entitled "TRANSLUMINAL MICRODISSECTION DEVICE," the disclosure of
which is incorporated herein by reference.
[0004] In the commercially available device described in U.S. Pat.
No. 4,990,134, known as the Rotablator.RTM., an ellipsoidal burr
coated with tiny diamond chips is rotated at a speed of at least
approximately 155,000 revolutions per minute. The burr is connected
to a drive motor capable of high speed rotation via a hollow,
flexible, helically-wound drive shaft, and is routed through the
blood vessel over a narrow guide wire that extends through the
central bore of the burr and its drive shaft. When this device is
operated, the burr preferentially cuts hard, inelastic material
(plaque) while sparing soft, elastic material (tissue) and
generates microscopic debris fragments that are sufficiently small
in size so as to pass through even the narrowest vascular channels
(capillary beds) without clogging them.
[0005] This Rotablator.RTM. atherectomy device, as well as any
other microdissection device that involves rotational ablation,
necessarily generates thermal energy during its rotation. For this
reason, as disclosed in U.S. Pat. No. 4,990,134, a biocompatible
saline solution is infused through a plastic sheath within which
the drive shaft rotates, to cool the sliding interface during
operation.
[0006] In addition to performing a cooling function, some
lubrication is needed to prevent wear caused by rotational friction
between the guide wire and the drive shaft or between the drive
shaft and the plastic sheath. The major factors that affect wear in
this type of rotational contact are load, temperature, surface
speed, surface finish, surface hardness, contact area, time, and
the type, amount, and viscosity of the lubricant.
[0007] During extended operation of the device, however, additional
lubrication should be provided to sustain the performance of the
guide wire, the drive shaft, and the sheath. Such a lubricant, if
infused through the device from outside the patient's body, must of
course, be non-toxic and safe for arterial use. In addition, to be
effective in use with the Rotablator.RTM. advancer/guide wire
system, the lubricant should be able to withstand shear stresses at
50.degree. C. and should not promote the agglomeration of ablated
plaque particles.
[0008] Injectable oil-in-water emulsions are currently being used
for two clinical applications. The first is for parenteral or
intravenous nutrition, as a source of fat calories and essential
fatty acids. Examples include Intralipid.RTM., available from
Pharmacia and Upjohn, and Liposyn.RTM., available from Abbott
Laboratories. Emulsions are also being used as a vehicle for poorly
water-soluble lipophilic drugs that cannot be injected directly.
Examples include Diprivan.RTM., containing the anesthetic drug
propofol, and Diazemuls.RTM., containing the drug diazepam.
[0009] Lipid emulsions are inherently unstable. No commercially
available lipid emulsion is stable following dilution in
physiological (0.9% w/v) salt solution. This instability is
manifested by formation of large droplets of non-emulsified oil on
the surface as well as by a shift in droplet size distribution
towards much larger diameters. Such changes often occur within the
first hour following dilution in saline and are accelerated by
heating or by applying any shear force. The relatively low pH and
high ionic strength of saline contributes to this effect.
[0010] Commercial lipid emulsions separate into oil and water
layers upon thawing after storage at freezing temperatures. For
this reason, special care must be taken when shipping in winter
through geographic areas having below freezing temperatures. It is
preferred that the lubricant be an emulsion which is stable in
saline and stable upon freezing with subsequent thawing. The
present invention meets these needs and overcomes other
deficiencies in the prior art.
[0011] What would be desirable is an improved, pharmacologically
compatible medical lubricant that is capable of delivering
therapeutic agents to target locations within the body. What has
not been provided in the prior art is an injectable medical
lubricant suitable for lubricating, rotating, and otherwise moving
medical devices, where the lubricant can optionally act as a
carrier for therapeutic agents to thereby yield a therapeutic
effect to a treatment site in the body.
SUMMARY OF THE INVENTION
[0012] The present invention includes a medical lubricant suitable
for injection into a patient. The lubricant is an oil-in-water
emulsion including an oil, a surfactant, a co-surfactant and water.
The lubricant preferably also includes a cryogenic agent, a pH
buffer, and a preservative. The lipid emulsion preferably has a
mean particle or droplet diameter of less then 1 micrometer, most
preferably less than about 0.5 micrometer. The lubricant can be
subjected to substantial shear by a rotating member, exhibits a
commercially acceptable shelf life during storage under ambient
temperatures, and is able to withstand freeze-thaw cycles without
substantial degradation. The lubricant can be diluted in
physiological saline for injection and maintains suitable emulsion
droplet size after such dilution.
[0013] The oil can be a vegetable oil or a medium chain
triglyceride. The preferred oil is refined olive oil, which
preferably comprises mostly mono-unsaturated oleic acid. The oil
can lubricate medical devices, such as rotating drive shafts in
atherectomy devices, thereby reducing wear on moving parts. A mean
droplet size of less than about 1 micrometer allows injection into
the bloodstream and subsequent absorption by the body without ill
effect. The emulsion most preferably includes about 20 g refined
olive oil per 100 mL emulsion.
[0014] The surfactant can be a phospholipid, preferably purified
egg yolk phospholipids. The surfactant stabilizes the oil droplets
dispersed in the continuous aqueous phase. The present invention
preferably includes about 1.2 g egg yolk phospholipids per 100 mL
emulsion.
[0015] The co-surfactant can be a salt of a bile acid, most
preferably sodium deoxycholate. The co-surfactant significantly
improves droplet stability after saline dilution, heating, and
exposure to high shear forces. Droplet stability includes the
resistance to formation of larger droplets, creaming, and formation
of a separate oil layer. Bile salt, acting in conjunction with
glycerin, provides improved freeze-thaw stability. Applicants
believe the bile salt also improves lubricity by acting as a
wetting agent, improving the coating of moving metal parts. The
present invention most preferably includes about 0.4 g bile salt
per 100 mL emulsion.
[0016] The cryogenic agent can be refined propylene glycol or
glycerin, preferably glycerin. Glycerin also provides improved
lubricity. The present invention preferably includes about 10 g
glycerin per 100 mL emulsion.
[0017] The pH buffer imparts improved droplet stability in a saline
diluent. Any physiological pH buffer may be used. When the pH
buffer is an amino acid buffer, said amino acid buffer usually has
a concentration of less than 0.20 g/100 mL emulsion. The amino acid
buffer is most preferably L-histidine in a concentration of about
0.16 g per 100 mL emulsion.
[0018] The preservative is preferably a heavy metal chelator such
as disodium EDTA. EDTA, and the histidine buffer, serve as
antioxidants, protecting unsaturated fatty acids found in egg yolk
phospholipids. The antioxidants provide an extended shelf life for
the emulsion at room temperature and inhibit peroxide formation
during clinical use. Disodium EDTA is preferably present in about
0.014 g per 100 mL emulsion.
[0019] The emulsion preferably has the pH adjusted to between about
8.3 and 8.8, with a base such as sodium hydroxide. This pH range
optimizes the emulsion stability in the presence of non-buffered
saline, which is slightly acidic. Sodium hydroxide can be present
in about 3.0 mEq per liter of emulsion.
[0020] An emulsion according to the present invention can be
prepared by combining refined olive oil, 1.2% egg yolk
phospholipid, 0.16% L-histidine (10 mM), 0.014% disodium EDTA (0.5
mM), and water, followed by ultrasonic processing for about 15
minutes. The emulsion can also be prepared using high pressure
homogenization techniques well known to those skilled in the
art.
[0021] In use, the emulsion can be stored for at least eighteen
(18) months, preferably twenty-four (24) months at room
temperature. The emulsion can be stored frozen at -30.degree. C.,
and then thawed without causing significant changes in droplet size
distribution. The emulsion can be added to normal, unbuffered 0.9%
saline solution. One anticipated use is injection of the emulsion
into an IV bag of saline, thereby diluting the emulsion. The
diluted emulsion can be infused from the IV bag through a catheter
tube housing a rotating member, such as an atherectomy drive shaft
or an ultrasonic probe drive shaft. The emulsion serves to
lubricate the moving parts and can thereafter enter the blood
stream of a patient without ill effect.
[0022] In certain embodiments of the invention, the above described
medical lubricant additionally includes one or more therapeutic
agents to thereby provide a therapeutic effect to a treatment site
in the body. One or more of the therapeutic agents may include a
genetic material encoding a therapeutic agent, a non-genetic
therapeutic material, proteins or cells that produce a therapeutic
effect. The choice of therapeutic agent will depend on the
application. In one embodiment where the lubricant is used in
conjunction with an atherectomy device, one or more of the
therapeutic agents inhibits cell proliferation and provides an
anti-restenosis effect. In other embodiments where the lubricant is
used in conjunction with a transmyocardial revascularization (TMR)
device or percutaneous myocardial revascularization (PMR) device,
one or more of the therapeutic agents promotes angiogenesis.
[0023] In yet another aspect of the invention, a method is provided
for lubricating an intravascular device. The inventive method
involves first preparing a patient for a medical procedure and then
inserting into the patient a medical device that is in need of
lubrication. A medical oil emulsion lubricant is infused into the
patient during the insertion and/or operation of the medical
device. The medical oil emulsion lubricant contains olive oil, an
egg yolk phospholipid, a bile salt, an amino acid buffer, and a
desired therapeutic agent. In one embodiment of the method the
medical procedure is atherectomy and the medical device is an
intravascular device that is capable of differentially removing
intravascular deposits from the walls of an artery. During the
atherectomy procedure, the therapeutic agent present in the medical
oil emulsion lubricant usually contains a cell proliferation
inhibitor that provides an anti-restenosis effect. In another
embodiment of the lubrication method, the medical procedure is
myocardial revascularization and the medical device is a myocardial
revascularization device. During the myocardial revascularization
procedure it is usual to include in the medical lubricant a
therapeutic agent that promotes angiogenesis.
DETAILED DESCRIPTION
[0024] In a preferred embodiment of the invention, the oil-in-water
emulsion lubricant comprises a mixture of water, oil, a surfactant,
a co-surfactant, a phospholipid, a cryogenic agent, a pH buffer and
a preservative.
[0025] Preferably the oil used in the lipid emulsion lubricant is a
liquid at room temperature, most preferably olive oil.
[0026] Chemically, olive oil contains mostly mono-unsaturated oleic
acid. Different oil bases, such as either soybean oil, which
contains a mixture of polyunsaturated fatty acids, mainly C.sub.14
C.sub.16, and C.sub.18, or medium chain triglycerides (MCT) may
also be used, especially with varying concentrations of the other
ingredients and with different surfactants. Almond oil, coconut
oil, corn oil, cotton seed oil, marine oil, palm kernel oil, peanut
oil, safflower oil, sesame oil, sunflower oil, and physical or
interesterified mixtures thereof can also be used. These other oil
bases, however, are not as effective as olive oil. Quite
surprisingly, we found that olive oil emulsions lubricate better
than soybean oil emulsions. The lubricant reduces wear on moving
components. In a preferred embodiment of the invention, the
concentration of olive oil in the lubricant is from about 5 to
about 40 g/100 mL emulsion, more preferably about 15 to about 25
g/100 mL emulsion, and is most preferably about 20 g/100 mL
emulsion.
[0027] An emulsion is a dispersion of one immiscible liquid within
another, commonly oil in water. An emulsifier is a surface active
agent designed to coat and stabilize the dispersed droplets against
coalescence. However, in certain formulations, this dispersion is
insufficiently stabilized by the primary emulsifier that is
typically added at concentrations of about 1-5% w/v. In such cases,
a second surface active agent, known as a co-surfactant, may be
added. A co-surfactant is typically used at a fractional
concentration of the primary emulsifier, e.g., 0.1-1.0%. In
principle, co-surfactants are added to accomplish specific tasks
such as enhancing electrostatic surface charge on the dispersed
droplets or strengthening the interfacial film between oil and
water. In reality, it is quite difficult to predict in advance
which co-surfactant, if any, will stabilize a novel emulsion
formulation under specific environmental conditions.
[0028] A primary emulsifier in the lipid emulsion lubricant could,
for example, be selected from a group of phospholipids such as soy
bean or egg yolk phospholipids. A preferred phospholipid is egg
yolk phospholipid, preferably present in a concentration of about
0.3 to about 3 g/100 mL emulsion, more preferably about 0.6 to
about 1.8 g/100 mL emulsion, most preferably about 1.2 g/100 mL
emulsion.
[0029] The co-surfactant could be, for example, PEG-400
(polyethylene glycol), Pluronic F68 (a non-ionic,
polyoxethylene-polyoxypropylene block copolymer, BASF), dimyristyl
phosphatidyl glycerin (DMPG), or the salt of a bile acid. When
PEG-400 is used, it can be present at about 5% weight/volume. When
Pluronic F68 is used, it can be present at about 1% weight/volume.
Preferably, the co-surfactant is the salt of a bile acid such as
cholic acid, deoxycholic acid, taurocholic acid, or mixtures
thereof. Most preferably, the co-surfactant is sodium deoxycholate,
as it is somewhat more effective in reducing wear than DMPG. In the
present invention, the superiority of sodium deoxycholate over
other tested co-surfactants was unexpected and unpredicted. In a
preferred embodiment, sodium deoxycholate is present at a
concentration of about 0.04 to about 4 g/100 mL emulsion, more
preferably about 0.2 to about 0.8 g/100 mL emulsion, most
preferably about 0.4 g/100 mL emulsion.
[0030] A preferred cryogenic agent is refined propylene glycol or
glycerin, most preferably glycerin. Glycerin serves to provide
freeze tolerance and improves the overall lubricating properties of
the emulsion. Glycerin is preferably present at a concentration of
about 1 to about 30 g/100 mL emulsion, more preferably about 2 to
about 20 g/100 mL emulsion, most preferably about 10 g/100 mL
emulsion.
[0031] A preferred pH buffer is an amino acid buffer, for example,
alanine, aspartic acid, glycine, histidine, isoleucine, leucine,
methionine, phenylalanine, proline, serine, valine, or mixtures
thereof. Often the amino acid buffer is present at a concentration
lower than about 0.20 g/100 mL. A preferred amino acid buffer is
histidine. Histidine contributes significant pH buffering capacity
in the critical pH 6 to 8 range, having a PK.sub.a of about 6.0.
This pH buffering contributes to emulsion stability after dilution
in saline. In addition, histidine serves as an antioxidant,
specifically a hydroxy radical scavenger. Histidine is preferably
present at a concentration of about 0.01 to about 1 g/100 mL
emulsion, more preferably about 0.05 to about 0.3 g/100 emulsion,
most preferably about 0.16 g/100 mL emulsion.
[0032] A preferred preservative is a heavy metal chelator such as
disodium EDTA. The combination of EDTA and histidine serves as a
potent antioxidant to protect unsaturated fatty acids found in egg
yolk phospholipids. This antioxidant system serves both to protect
the emulsion in the bottle during prolonged storage at room
temperature as well as to inhibit peroxide formation during
clinical use. Disodium EDTA is preferably present at a
concentration of about 0.001 to about 0.1 g/100 mL emulsion, more
preferably about 0.01 to about 0.05 g/100 mL emulsion, most
preferably about 0.014 g/100 mL emulsion.
[0033] Finally, sodium hydroxide can be added to titrate the
emulsion to a final pH of about 8.3 to about 8.8. This pH range is
chosen to optimize emulsion stability in the presence of
non-buffered saline, which is slightly acidic.
[0034] In order to manufacture the present invention, a mixture of
water-for-injection with the ingredients listed above in the
amounts described can be passed through a high pressure
homogenizer. The resulting mixture is an opaque white, milky liquid
that is a suspension of small oil droplets in water, with a normal
droplet size distribution. The droplet size has a mean of about 0.4
.mu.m and a maximum of about 4 .mu.m. The distribution includes 90%
of droplets less than about 0.65 .mu.m and less than 0.5% of
droplets greater than 1 .mu.m. Even after experiencing high shear,
all droplets remain less than about 5 .mu.m.
[0035] The lubricant is to be shipped in sterile vials and injected
into a sterile saline intravenous (IV) bag prior to use. During a
rotational atherectomy procedure, the lubricant can be infused
through the catheter of a Rotablator.RTM. system and then into the
coronary artery. Because the present invention is safe for
parenteral use, it is a potential lubricant for any device
operating inside the human body. Examples of this are:
interoperative milk into which endoscopic equipment is dipped
before placement into the human body; coating for sutures in order
to reduce friction; lubricant for heart valves in order to ease
placement during surgery; lubricant for ultrasonic catheters; and
lubricant for other future devices that employ swiftly-moving parts
within the body. In addition, the medical lubricants of the present
invention can also be used during placement in the body of catheter
like tubes such as are used, for example during atherectomy,
transmyocardial revascularization, angioplasty, and the like. The
medical lubricant emulsions facilitate the advancement of the
catheter in a blood vessel by lubrication of the contact zone
between the catheter and the blood vessel. The medical lubricants
of the invention can similarly be used to ease the placement and
advancement of medical devices through the catheter to a site of
use in the body in addition to lubricating moving parts within the
medical device. The inventive medical lubricants can also contain
therapeutic agents that are introduced via a catheter into the body
to a specific target location. The medical lubricant emulsion can
be infused into the body through a catheter or through a medical
device that is located inside a guide catheter.
[0036] Depending on the application, the medical lubricant
optionally includes one or more therapeutic agents such as a
genetic material, a non-genetic therapeutic material, or cells.
[0037] Examples of therapeutic agents used in accordance with the
invention include, but are not limited to: anti-thrombogenic agents
such as heparin, heparin derivatives, urokinase, and PPack
(dextro-phenylalanine-proline-arginine-chloromethylketone);
anti-proliferative agents such as enoxaprin, angiopeptin, or
monoclonal antibodies capable of blocking smooth muscle cell
proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory
agents such as dexamethasone, prednisolone, corticosterone,
budesonide, estrogen, sulfasalazine, and mesalamine;
antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin and thymidine kinase
inhibitors; anesthetic agents such as lidocaine, bupivacaine, and
ropivacaine; anti-coagulants such as
D-Phe-Pro-Arg-chloromethylketone, an arginine-glycine-aspartic acid
(RGD) peptide-containing compound, heparin, antithrombin compounds,
platelet receptor antagonists, anti-thrombin antibodies,
anti-platelet receptor antibodies, aspirin, prostaglandin
inhibitors, platelet inhibitors, and tick antiplatelet peptides;
vascular cell growth promoters such as growth factor inhibitors,
growth factor receptor antagonists, transcriptional activators of
genes encoding vascular cell growth promoter proteins, and
translational activators of mRNAs encoding vascular cell growth
promoter proteins; vascular cell growth inhibitors such as growth
factor inhibitors, growth factor receptor antagonists,
transcriptional repressors of genes encoding vascular cell growth
inhibitors, translational repressors of mRNAs encoding vascular
cell growth inhibitors, DNA replication inhibitors, vascular cell
growth inhibitory antibodies, antibodies directed against growth
factors, bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; cholesterol-lowering agents; vasodilating agents; and
agents which interfere with endogenous vascoactive mechanisms.
[0038] In embodiments in which the therapeutic agent includes a
substantially purified genetic material, useful polynucleotide
sequences include, for example, DNA or RNA sequences having a
therapeutic effect after being taken up by a cell. Examples of
therapeutic polynucleotides include anti-sense DNA and RNA; DNA
coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to
replace defective or deficient endogenous molecules. The
polynucleotides useful in the invention can also code for
therapeutic polypeptides. A therapeutic polypeptide is understood
to be any substantially purified translation product of a
polynucleotide regardless of size, and whether glycosylated or not.
Therapeutic polypeptides include, as a primary example, those
polypeptides that can compensate for a defective or deficient
species in an animal, or those that act through toxic effects to
limit or remove harmful cells from the body. In addition, the
polypeptides or proteins that can be incorporated into the coating
material of the present invention, or whose DNA can be
incorporated, include, without limitation, angiogenic factors
including acidic and basic fibroblast growth factors, vascular
endothelial growth factor, epidermal growth factor, transforming
growth factor .alpha. and .beta., platelet-derived endothelial
growth factor, platelet-derived growth factor, tumor necrosis
factor .alpha., hepatocyte growth factor and insulin like growth
factor; growth factors; cell cycle inhibitors including CD
inhibitors; thymidine kinase ("TK") and other agents useful for
interfering with cell proliferation, including agents for treating
malignancies. Still other useful factors, which can be provided as
polypeptides or as DNA encoding these polypeptides, include the
family of bone morphogenic proteins ("BMPs") See, for example, U.S.
Pat. Nos. 5,948,428, 5,658,882 and 5,393,739. The known proteins
include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1),
BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and
BMP-16. Currently, preferred BMPs are any of BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as
homodimers, heterodimers, or combinations thereof, alone or
together with other molecules. Alternatively or, in addition,
molecules capable of inducing an upstream or downstream effect of a
BMP can be provided. Such molecules include any of the "hedgehog"
proteins, or the DNAs encoding them.
[0039] In other embodiments, one or more of the therapeutic agents
include cells. The therapeutic cells can be of human origin
(autologous or allogeneic) or from an animal source (xenogeneic).
The cells may be genetically engineered if desired to deliver
proteins of interest at the site of cell deposition. The medical
lubricant is preferably formulated as needed to maintain cell
function and viability.
[0040] In a preferred embodiment, the medical lubricant is used in
conjunction with an atherectomy device and includes a therapeutic
agent that inhibits restenosis. In this embodiment, the therapeutic
agent inhibits smooth muscle cell proliferation and comprises a
therapeutic agent such as paclitaxel.
[0041] In another embodiment, the medical lubricant is used in
conjunction with a mechanical transmyocardial revascularization
procedure, such as described in U.S. Pat. No. 5,968,059, which is
incorporated herein by reference. The medical lubricants of the
present invention are used to lubricate the moving parts of the
mechanical transmyocardial revascularization device during
performance of the procedure. Alternatively, the inventive medical
emulsions can be used in conjunction with other transmyocardial and
percutaneous myocardial revascularization devices that utilize a
variety of different means to introduce myocardial wounds, such as,
for example, a laser transmyocardial revascularization device (U.S.
Pat. Nos. 5,925,033 and 5,885,272), a radio frequency
transmyocardial revascularization device (U.S. Pat. No. 5,938,632),
a cyro transmyocardial revascularization device (U.S. Pat. No.
5,993,444) or an electrode percutaneous myocardial
revascularization device (PCT Patent Application No.
PCT/US99/04942). Introduction of a medical lubricant of the present
invention during a myocardial revascularization procedure may be
desirable to lubricate movement of the myocardial ablation device
through a tubular delivery catheter as well as during placement of
the catheter itself into the patient. In this embodiment of the
invention, the medical lubricant preferably comprises a therapeutic
agent that promotes angiogenesis such as growth factors, vascular
endothelial growth factors, and DNA that encodes these growth
factors.
Experimental Results
[0042] Sample Preparation
[0043] Four one-liter lots of 20% olive oil emulsion were prepared,
with each 100 mL of emulsion containing: 20.0 g olive oil, 1.2 g
egg yolk phospholipid (a surfactant), 0.40 g sodium deoxycholate (a
bile salt co-surfactant), 0.16 g L-histidine (an amino acid pH
buffer), and 0.014 g disodium EDTA (a preservative). 3.0 mEq/L NaOH
was also added to adjust pH. The four lots varied only in glycerin
content (a cryogenic agent) in the amounts specified in Table 1.
Intralipid, a commercially available lipid emulsion for parenteral
nutrition, is included in Table 1 for comparison. Intralipid 20%
contains 20% w/v soybean oil, egg yolk phospholipids, glycerin,
sodium hydroxide, and water for injection (WFI).
1TABLE 1 Glycerin Concentration, Osmolality and Zeta Potential
Glycerin Conc., Osmolality, Lot Number Grams/100 mL mOsm/kg Zeta
Potential, mv Intralipid 20% 2.25 350* -38 HT-049 1.6 280 -46
HT-050 10.0 300 -48 HT-051 20.0 322 -44 HT-052 30.0 346 -40
*undiluted sample
[0044] High glycerin concentrations are expected to elevate
osmolality and depress the freezing point. The original formulation
was designed with 1.6% glycerin to produce an isotonic product,
having about 280-320 mOsm/kg. As osmolality could not be measured
directly in higher concentration glycerin samples using the
freezing point depression method, osmolality was measured after a
1:50 dilution in 0.9% saline. This dilution was chosen to represent
expected clinical practice. The osmolality of the Intralipid was
measured on an undiluted sample.
[0045] The Zeta potential or net surface charge is an important
determinant of stability in colloidal systems. Zeta was calculated
from microelectrophoretic mobility in 5 mM Hepes buffer at pH 8.0
using a laser light scattering detection system (Malvern
ZetaSizer). Control (non-frozen) samples were used. As can be seen
in Table 1, Zeta potential was most negative at about 10% glycerin
concentration.
[0046] Visual Inspection
[0047] At least three separate bottles from each lot were visually
inspected for homogeneity and surface oil. Inspections were
performed on initial samples about one week after sterilization and
on samples that had been subjected to freeze/thaw and shipping.
"Creaming" refers to the rapid floatation (e.g., within an hour) of
large, emulsified oil droplets formed either by coalescence or by
aggregation of smaller emulsified droplets. In contrast, surface
oil ("free oil") droplets are not emulsified. The results of visual
inspection are summarized in Table 2. As can be seen in Table 2,
Lot HT-050, having 10% glycerin, had no surface oil and no
creaming, either initially or after the freeze/thaw cycle.
2TABLE 2 Visual Examination Post Freeze/Thaw Lot No. Initial
(non-frozen) (all temperatures) HT-049 no surface oil; no creaming
no surface oil; rapid formation of cream layer HT-050 no surface
oil; no creaming no surface oil; no creaming HT-051 a few oil
droplets (.ltoreq.1 mm); a few oil droplets (.ltoreq.1 mm); no
creaming no creaming HT-052 no surface oil; no creaming no surface
oil; no creaming
[0048] Freeze/Thaw and Stress Testing
[0049] Measurements of pH and droplet size were performed on
triplicate samples from each lot. Test samples were subjected to
freeze/thaw and shipping. Control samples were subjected to no
freezing, only shipping. Both control and freeze/thaw samples were
subjected to a saline/heat/shear stress test. This test involves a
1:20 dilution in 0.9% saline, followed by heating in a 40.degree.
C. water bath for 5 minutes, and ending with 3 minute high-shear
processing by a rotor-stator device (Ultra Turrax, 20,500 rpm) at
40.degree. C. Due to significant deterioration (creaming),
freeze/thaw samples from Lot HT-049 (1.6% glycerin) were not
subjected to this test. Some of the data for Intralipid 20% and Lot
HT-050 (10% glycerin) are summarized in Table 3.
[0050] Table 3 contains the results: pH (before and after
freeze/thaw for Lot HT-050); pH after dilution/heat/shear; mean
droplet diameter before and after dilution/heat/shear; droplet
diameter for which 90% of the droplets have a smaller diameter
before and after dilution/heat/shear; droplet diameter for which
100% of the droplets have a smaller diameter before and after
dilution/heat/shear; and the percent of droplets having a droplet
diameter greater than 1 micrometer before and after
dilution/heat/shear.
[0051] Inspection of Table 3 shows a significant increase in
droplet diameter after dilution/heat/shear stress for Intralipid
20%. As previously discussed, freeze/thaw of Intralipid 20% results
in phase separation. Lot HT-050 (10% glycerin) in the control
(before freeze/thaw) shows a very slight increase in droplet
diameter at the 90th percentile and a maximum droplet size of 4.30
micrometers due to dilution/heat/shear. This compares with an
Intralipid increase from 0.80 to 1.23 micrometers droplet diameter
at the 90th percentile, and maximum droplet size of 12.2
micrometers due to dilution/hear/shear. Freeze/thaw had an
insignificant effect on droplet size for the Lot HT-050 sample.
Freeze/thaw also had no significant change on the effects of
dilution/heat/shear on the HT-050 sample after thawing.
3TABLE 3 Effects of Freeze/Thaw and Heat/Shear on 20% Olive Oil
Emulsions Heat/ Heat/ Heat/ Lot No./ Heat/ Mean Shear Shear Shear
Heat/ Storage Shear Dia, Mean 90% 90% 100% 100% % Shear Condition
pH pH .mu.m Dia <.mu.m <.mu.m <.mu.m <.mu.m <1 .mu.m
% <1 .mu.m Intralipid 7.85 6.70 0.49 0.67 0.80 1.23 3.49 12.2
4.6 13.9 20%/Control 50/Control 8.63 7.42 .040 .042 0.61 0.65 1.51
4.30 0.50 3.4 50/Frozen @ 8.64 7.54 0.40 0.41 0.61 0.64 1.51 4.30
0.50 2.6 -30.degree. C.
[0052] Phase-Contrast Microscopy
[0053] The samples were also observed under phase-contrast
microscopy. Freeze/thaw samples from HT-049 (1.6% glycerin) showed
a very large number of coalesced and aggregated oil droplets. In
contrast, all elevated glycerin samples, HT-050 (10% glycerin),
HT-051 (20% glycerin), and HT-052 (30% glycerin) had a very
uniform, clean appearance with no large droplets. Samples were also
observed after the saline/heat/shear stress test. Samples from all
olive oil lots looked excellent, while the Intralipid samples
showed many large coalesced droplets. These observations are
consistent with the drop size distribution data shown in Table
3.
[0054] Sample Test Summary
[0055] The addition of glycerin at 10% weight/volume appears
sufficient to protect the olive oil emulsions from freeze/thaw
damage for at least 48 hours, even at minus 30 degrees C. In this
respect, no advantages were seen with higher concentrations of
glycerin. The presence of elevated glycerin concentration had no
significant effect on product appearance, pH, drop size
distribution or Zeta potential. In contrast, the 1.6% glycerin
sample (ET-049) exhibited severe creaming following freeze/thaw.
The complete preservation of emulsion quality during freeze/thaw
using only 10% w/v glycerin (e.g., lot #HT-50) was quite surprising
and unexpected. Since samples stored at -30.degree. C. appear to be
frozen solid, glycerin is not acting as a simple antifreeze agent.
Cryopreservation must be occurring by an action at the oil-water
interface of the dispersed droplets, i.e., in the phospholipid
monolayer.
[0056] The addition of each 10% of glycerin, after a 50-fold
dilution in 0.9% saline, adds about a 20 mOsm/kg increment in
osmolality. Thus, even a 30% glycerin emulsion has a diluted
osmolality no higher than undiluted Intralipid 20%. Therefore no
tonicity problems are expected in clinical applications.
[0057] Utility
[0058] The utility of the invention was tested using the Rotoblator
system. This system rotates a 135 cm stainless steel drive coil
with an attached diamond coated burr over a 0.009 inch diameter
stainless steel guide wire at 180,000 rpm. The system in current
use is lubricated during startup with a thin film of HYSTRENE on
the guide wire and throughout the operation by a continuous
infusion of normal saline. This allows for efficient operation for
only limited duration, as the lubricant washes away and is not
replenished, therefore the performance can start to degrade as the
device starts operating. Performance degradation can take the form
of loss of speed, heat build-up, guide wire wear, drive coil wear,
burr wear and reduced axial mobility.
[0059] Optimally, for use with the Rotoblater Advancer/guide wire
system, the lubricant should withstand high shear stress at
50.degree. C. without emulsion degradation. All emulsion droplets
should remain less than 5 micrometers in diameter, even after shear
stress associated with use of this device. In addition, a mixture
of the emulsion in saline should remain stable after overnight
storage at room temperature and be non-toxic.
[0060] Wear and Speed Stability Test
[0061] Lubricants were tested using the Rotoblater advancer. An
advancer having a 1.75 mm burr was passed through a PTFE tube with
a 2.2 mm ID, which is wrapped over a pair of mandrels to create a
fixed "S"-shaped path. The guide wire distal end is placed about 2
inches past the burr and the fixture immersed in a 37.degree. C.
water bath and run for 5 minutes. The lubricants tested included
both normal saline and saline mixed with 20 cc per liter of the
olive oil emulsion. The advancer speed was recorded and the wear
scars on the guide wire wear measured with a Laser Micrometer. With
saline alone, average wear was 0.0048 inch compared with only
0.0001 inch wear for saline with the emulsion added. With saline
alone, the average speed change was a decrease of 13,877 rpm,
compared with an average increase of 79 rpm for saline with the
emulsion added. Thus, both guide wire wear and speed stability
improved with the emulsion added.
[0062] Tortuous Advance Force Test
[0063] Another series of tests was performed, similar to the
previous study but having a more tortuous path, to simulate the
path of a coronary vessel. The burr was advanced and retracted over
an S-shaped bend throughout the 5 minute test. The test measured
the force required to advance and retract the burr, the advancer
speed, and the fluid temperature downstream of the burr in the PTFE
tube. With saline alone, the rpm decreased by 13,000 rpm compared
with an increase of 800 rpm for saline with emulsion. With saline
alone, the peak fluid temperature was 58.degree. C. compared with
47.5.degree. C. for saline with emulsion. With saline alone, 170 gm
of force was required at the peak to advance the device, compared
with 120 gm for saline with emulsion. Thus, the emulsion provided
improved lubrication over saline alone.
[0064] Comparison with Other Lipid Emulsions
[0065] Another study was performed using stainless steel rods with
surface speeds and pressures similar to those found in the
Rotoblater. A series of emulsions of olive oil and Intralipid was
tested for wear resistance and emulsion stability. The average wear
scars using Intralipid were 64 millionths of an inch +/-16,
compared to only 5 millionths of an inch +/-11 for olive oil
emulsions. Furthermore, the olive oil emulsion showed insignificant
post shear changes in droplet size distribution, the mean droplet
diameter remaining about 0.4 micrometers. In distinct contrast, the
Intralipid lubricant showed a dramatic degradation in the emulsion,
including an increase in maximum droplet diameter to about 10
micrometers, an increase in mean droplet diameter to about 0.8
micrometers, an increase in 90th percentile droplet diameter from
about 0.8 micrometers to about 2 micrometers, and a bimodal
distribution in droplet diameter, having a second peak at about 2
micrometers.
[0066] Oil Emulsions Comparison Tests
[0067] A series of oil emulsion samples was prepared, all
containing 20% weight/volume oil, 1.2% egg yolk phospholipid, 0.16%
L-histidine (10 mM), and 0.014% disodium EDTA (0.5 mM). Additional
excipients in each sample are indicated in Table 4. Emulsions were
prepared by ultrasonic processing (Sonics and Materials Inc., 13 mm
horn, 200 mL sample volume, and 80% power for 15 minutes at 50%
duty cycle). Drop size distribution was determined by laser light
scattering (Malvern MasterSizer). Stainless steel wear testing was
expressed as a ratio of stainless steel volume lost with a saline
control divided by the volume lost with the test emulsion. Higher
ratios indicate less steel lost and therefore better
lubrication.
4TABLE 4 Olive Oil-in-Water Emulsion is Most Effective for
Lubrication Stainless Aqueous Mean Steel Prep Oil Phase, Additive
Sterile Dia, Wear, Saline No. 20% w/v % w/v pH .mu.m % > 1 .mu.m
Emulsion 1 MCT None 8.14 1.10 18.4 1.09 2 MCT Glycerin 8.25 0.95
16.8 1.56 2.25% 3 MCT PEG-400, 8.21 0.87 18.8 0.95 5.0% 4 MCT
Pluronic 8.24 0.49 4.2 1.88 F68, 1.0% 10 15% MCT None 8.11 0.75
18.4 2.53 5% Castor Oil 6 Olive None 8.20 0.65 13.0 23.71 9 SBO
None 8.25 0.81 25.6 7.12
[0068] As can be seen from inspection of Table 4, there was a
dramatic and unexpected advantage with respect to lubrication
efficiency using purified olive oil (Croda) as the emulsified lipid
phase versus other oils such as MCT (medium chain triglycerides).
Other studies (not shown) confirmed the superiority of olive
oil.
[0069] Co-surfactant Emulsion Stability Test
[0070] In order to be useful as a lubricant emulsion, the
injectable product must be stable for several hours after dilution
in unbuffered, normal, 0.9% saline solution. Therefore, a series of
samples having various aqueous co-surfactants was tested in a 20%
olive oil emulsion. The samples included a control having no
co-surfactant, PEG-400 added at 5%, Pluronic F68 (non-ionic block
copolymer) added at 1%, sodium deoxycholate (a bile salt) added at
0.2%, and Intralipid 20%. The emulsions were diluted 1:20 in 0.9%
saline and allowed to stand overnight at room temperature. Emulsion
quality was scored by monitoring the formation of large droplets (%
>1 micrometer) using a laser light scattering instrument. In
decreasing order of the percentage of droplets having a diameter
greater than 1 micrometer, Intralipid had 60%; Pluronic F68, 42%;
PEG-400, 37%; control 25%; and deoxycholate 6%. From several
experiments such as this, we concluded that the use of deoxycholate
as a co-surfactant best protects this olive oil emulsion following
saline dilution.
[0071] Diluted Intralipid Droplet Size Tests
[0072] Intralipid was evaluated for use as a lubricant in a
stainless steel wear test. Intralipid was evaluated after dilution
in Water For Injection (WFI), after dilution 1:20 in saline, and
after dilution in saline with heat/shear stress. The initial
Intralipid mean droplet diameter after dilution in WFI was 0.44
micrometer, compared with 2.07 after dilution in saline and 0.96
after dilution in saline with heat/shear stress. The initial
percentage of droplets greater than 1 micrometer in diameter was
2.6%, compared with 42.8% after dilution in saline and 26.1% after
dilution in saline with heat/shear stress. While Intralipid is a
safe and clinically acceptable intravenous nutrition product, it is
not useful as an injectable lubricant because this soybean oil
emulsion shows large oil droplets and creaming following saline
dilution/heat/shear stress.
[0073] Co-surfactant Saline Dilution/Heat/Shear Stress Tests
[0074] The percentage of large (greater than 1 micrometer)
droplets, both initially and after saline dilution/heat/stress
testing, was measured for emulsions having a series of
co-surfactants. Dimyristoylphosphatidylglyce- rin (DMPG), a charged
lipid, was added at 0.2%. Poloxamer 331, a lipophilic, non-ionic
block copolymer, was added along with DMPG in another sample.
Deoxycholate, a bile acid, was added at 0.4%. Poloxamer 331 was
added along with deoxycholate in another sample. Intralipid was
also tested.
[0075] The DMPG preparation initially had about 37% of droplets
with a diameter greater than 1 micrometer, deoxycholate about 14%,
poloxamer/deoxycholate and Intralipid about 3%, and poloxamer/DMPG
about 2%. The failure of DMPG to cause smaller droplet size was
unexpected since this lipid enhances the stabilizing
electronegative surface charge on dispersed droplets.
[0076] After saline dilution/heat/stress testing, however, DMPG had
about 37% of droplets with a diameter greater than 1 micrometer,
poloxamer/deoxycholate about 32%, Intralipid and poloxamer/DMPG
about 27%, and deoxycholate about 15%. Thus while some
co-surfactants provide a finer initial droplet size distribution
than deoxycholate, they provide much less protection against saline
dilution/heat/shear stress. From studies such as these, we
concluded that sodium deoxycholate is the most preferred
co-surfactant.
[0077] While the preferred embodiment of the invention has been
illustrated and described, it will be appreciated that various
changes can be made therein without departing from the spirit and
scope of the invention.
[0078] These corrections do not change the substance of the letter
or the opinion reached with regards to patentability of the
multi-vitamin S.E.T. compositions. The embodiments of the invention
in which an exclusive property or privilege is claimed are defined
as follows:
* * * * *