U.S. patent application number 12/219542 was filed with the patent office on 2009-01-15 for composition for an injectable bone mineral substitute material.
This patent application is currently assigned to Bone Support AB. Invention is credited to Lars Lidgren, Malin Nilsson.
Application Number | 20090018667 12/219542 |
Document ID | / |
Family ID | 20280508 |
Filed Date | 2009-01-15 |
United States Patent
Application |
20090018667 |
Kind Code |
A1 |
Lidgren; Lars ; et
al. |
January 15, 2009 |
Composition for an injectable bone mineral substitute material
Abstract
The invention refers to an injectable composition for a bone
mineral substitute material, which comprises a dry powder mixed
with an aqueous liquid. The powder comprises a first reaction
component comprising a calcium suphate hemihydrate with the
capability of being hardened to calcium sulphate dihydrate when
reacting with said aqueous liquid; a second reaction component,
which comprises a calcium phosphate with the capability of being
hardened to a calcium phosphate cement when reacting with said
aqueous liquid; and at least one accelerator for the reaction of
said first and/or second reaction component with said aqueous
liquid. A method of producing an injectable bone mineral substitute
material is also provided, wherein the composition is mixed in a
closed mixing and delivery system for delivery.
Inventors: |
Lidgren; Lars; (Lund,
SE) ; Nilsson; Malin; (Lund, SE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Bone Support AB
|
Family ID: |
20280508 |
Appl. No.: |
12/219542 |
Filed: |
July 23, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10333026 |
Oct 22, 2003 |
7417077 |
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PCT/SE01/01627 |
Jul 16, 2001 |
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12219542 |
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Current U.S.
Class: |
623/23.63 ;
128/898; 623/23.51; 623/23.61 |
Current CPC
Class: |
A61L 2430/02 20130101;
A61L 27/425 20130101; A61L 24/02 20130101; A61L 27/12 20130101;
A61L 24/0063 20130101; A61P 11/00 20180101; A61L 2400/06
20130101 |
Class at
Publication: |
623/23.63 ;
623/23.51; 623/23.61; 128/898 |
International
Class: |
A61F 2/28 20060101
A61F002/28; A61B 19/00 20060101 A61B019/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 17, 2000 |
SE |
0002676-5 |
Claims
1-33. (canceled)
34. A composition for a bone mineral substitute material comprising
a dry powder to be mixed with an aqueous liquid, the dry powder
comprising a first setting reaction component, which is a calcium
sulphate hemihydrate; a second setting reaction component, which is
a calcium phosphate; and at least one accelerator for the setting
reaction of both the first and the second setting reaction
components with the aqueous liquid, wherein the at least one
accelerator for the reaction of the second component with the
aqueous liquid is dissolved in the aqueous liquid.
35. The composition of claim 34, wherein the calcium sulphate
hemihydrate is an .alpha.-calcium sulphate hemihydrate.
36. The composition according to claim 34, wherein the calcium
phosphate is a tricalcium phosphate.
37. The composition according to claim 34, wherein the accelerator
is disodium hydrogen phosphate (Na.sub.2HPO.sub.4).
38. The composition according to claim 34, wherein the accelerator
comprises 0.1 wt % to 10 wt % of the aqueous liquid.
39. The composition according to claim 38, wherein the accelerator
comprises 1 wt % to 5 wt % of the aqueous liquid.
40. The composition according to claim 34, wherein the aqueous
liquid comprises distilled water or a balanced salt solution.
41. The composition of claim 34, wherein the aqueous liquid
comprises between 0.1 ml and 2 ml per gram of the powder.
42. The composition of claim 41, wherein the aqueous liquid
comprises between 0.5 ml and 1 ml per gram of the powder.
43. The composition of claim 34 further comprising a biologically
active substance.
44. The composition of claim 43, wherein the biologically active
substance is chosen from a growth factor, an anti-cancer substance,
an antibiotic, and an antioxidant, and mixtures thereof.
45. A composition for a bone mineral substitute material comprising
a dry powder to be mixed with an aqueous liquid, the dry powder
comprising a first setting reaction component, which is a calcium
sulphate hemihydrate; a second setting reaction component, which is
a calcium phosphate; at least one accelerator for the setting
reaction of the first or the second setting reaction component, or
both the first and the second setting reaction components with the
aqueous liquid, wherein the at least one accelerator for the
reaction of the second component with the aqueous liquid is
dissolved in the aqueous liquid, and a biologically compatible oil
to improve the injectability of the composition.
46. The composition of claim 45, wherein the calcium sulphate
hemihydrate is an .alpha.-calcium sulphate hemihydrate.
47. The composition according to claim 45, wherein the calcium
phosphate is a tricalcium phosphate.
48. The composition according to claim 45, wherein the biologically
compatible oil is vitamin E.
49. The composition according to claim 45, wherein the biologically
compatible oil comprises 0.1 wt % to 5 wt % of the composition.
50. The composition according to claim 49, wherein the biologically
compatible oil comprises 0.5 wt % to 2 wt % of the composition.
51. A composition for a bone mineral substitute material comprising
a dry powder to be mixed with an aqueous liquid, the dry powder
comprising a first setting reaction component, which is a calcium
sulphate hemihydrate; a second setting reaction component, which is
a calcium phosphate; at least one accelerator for the setting
reaction of the first or the second setting reaction component, or
both the first and the second setting reaction components with the
aqueous liquid, wherein the at least one accelerator for the
reaction of the second component with the aqueous liquid is
dissolved in the aqueous liquid; and a pH reducing component in
order to improve the injectability of the composition.
52. The composition of claim 51, wherein the calcium sulphate
hemihydrate is an .alpha.-calcium sulphate hemihydrate.
53. The composition of claim 51, wherein the calcium phosphate is a
tricalcium phosphate.
54. The composition of claim 51, wherein the pH reducing component
is ascorbic acid or citric acid.
55. The composition of claim 51, wherein the pH reducing component
comprises 0.1 wt % to 5 wt %.
56. The composition of claim 55, wherein the pH reducing component
comprises 0.5 wt % to 2 wt % of the composition.
57. A method of producing an injectable bone mineral substitute
material, wherein the composition of claim 34 is mixed with the
aqueous liquid in a closed mixing and delivery system.
58. The method of claim 57, wherein the mixing is conducted under
conditions of subatmospheric pressure.
59. A method of producing an injectable bone mineral substitute
material, wherein the composition of claim 51 is mixed with the
aqueous liquid in a closed mixing and delivery system.
60. The method of claim 59, wherein the mixing is conducted under
conditions of subatmospheric pressure.
61. A method of producing a composition for bone mineral substitute
material, comprising contacting the composition of claim 34 with an
aqueous liquid.
62. The method of claim 61, wherein the composition is capable of
being hardened in a body fluid in vivo to a bi-phasic cement
implant that with time obtains a porous structure for bone
ingrowth.
63. A kit for use in preparing a composition for a bone mineral
substitute material, said kit comprising: (1) the composition
according to claim 34; and (2) optionally an aqueous liquid.
Description
TECHNICAL FIELD
[0001] The present invention relates to an injectable composition
for a bone mineral substitute material with the capability of being
hardened in a body fluid in vivo. Furthermore, the invention
relates to a method of producing such a material.
BACKGROUND ART
[0002] During the last decade, the number of fractures related to
osteoporosis, i.e. reduced bone mass and changes in microstructure
leading to an increased risk of bone fractures, has almost doubled.
Due to the continuously increasing average life time it is
estimated that by 2020 people over 60 years of age will represent
25% of Europe's population and that 40% of all women over 50 years
of age will suffer from an osteoporotic fracture.
[0003] With the aim to reduce or eliminate the need for bone
grafting, research has been made to find a suitable artificial bone
mineral substitute. Presently, at least the following bone mineral
substitutes are used for the healing of bone defects and bone
fractures, namely calcium sulphates, as for instance Plaster of
Paris, calcium phosphates, as for instance hydroxylapatite, and
polymers, as for instance polmethylmetacrylate (PMMA).
[0004] Calcium sulphate (Plaster of Paris), CaSO.sub.41/2H.sub.2O,
was one of the first materials investigated as a substitute for
bone grafts. Studies have been undertaken since 1892 to demonstrate
its acceptance by the tissues and rapid rate of resorbtion. It has
been concluded that Plaster of Paris implanted in areas of
subperiosteal bone produces no further untoward reaction in the
tissue than normally is present in a fracture. Regeneration of bone
in the area of subperiosteal resection occurs earlier than when an
autogenous graft is used. Plaster of Paris does not stimulate
osteogenesis in the absence of bone periosteum. The new bone
growing into Plaster of Paris is normal bone. No side effects
attributable to the implantation of Plaster of Paris have been
noted in adjacent tissues or in distant organs. However, Plaster of
Paris has the drawback of very long setting times, which
constitutes problems at surgery.
[0005] Another group of materials for substituting bone tissue in
fracture sites and other bone defects is calcium phosphate cements.
Due to their biocompatibility and their osteoconductivity they can
be used for bone replacement and augmentation.
[0006] Hydroxylapatite, a crystalline substance which is the
primary component of bone, is mainly used as a bone substitute, but
is not strong enough for use under weight bearing conditions.
Experiments have shown that hydroxylapatite cement forms a stable
implant in respect of shape and volume over 12 months and has the
same excellent tissue compatibility as exhibited by commercial
ceramic hydroxylapatite preparations. Microscopic examination
clearly demonstrated that hydroxylapatite cement was progressively
ingrown by new bone over time.
[0007] Although the ideal is to achieve hydroxylapatite, there are
also apatite-like calcium phosphates which can be obtained as
potential bone substitutes. In Table 1 calcium phosphates are
presented which are formed by a spontaneous precipitation at room
or body temperature, as well as the pH range, within which these
components are stable.
TABLE-US-00001 TABLE 1 Calcium phosphates obtained by precipitation
at room or body temperature Ca/P Formula Name pH 0.5
Ca(H.sub.2PO.sub.4).cndot.H.sub.2O MCPM 0.0-2.0 1
CaHPO.sub.4.cndot.2H.sub.2O DCPD 2.0-6.0 1.33
Ca.sub.8(HPO.sub.4).sub.2,(PO.sub.4).sub.4.cndot.5H.sub.2O OCP
5.5-7.0 1.5 Ca.sub.9(HPO.sub.4)(PO.sub.4).sub.5OH CDHA 6.5-9.5 1.67
Ca.sub.5(PO.sub.4).sub.3OH PHA 9.-5-12
[0008] Other calcium phosphates can be obtained by means of
sintering temperatures, above 1000.degree. C. (Table 2). These
calcium phosphates can not be obtained by precipitation in room or
body temperature. However, they can be mixed with an aqueous
solution alone or in combinations with other calcium phosphates to
form a cement-like paste which will set with time.
TABLE-US-00002 TABLE 2 Components forming calcium phosphate cements
Ca/P Compound Formula Name 1.5 .alpha.-tricalcium phosphate
.alpha.-Ca.sub.3(PO.sub.4).sub.2 .alpha.-TCP 1.5 .beta.-tricalcium
.beta.-Ca.sub.3(PO.sub.4).sub.2 .beta.-TCP 1.67 Sintered
hydroxylapatite Ca.sub.10(PO.sub.4).sub.6(OH).sub.2 SHA 2.0
Tetracalcium phosphate Ca.sub.4(PO.sub.4).sub.2O TTCP
[0009] Bone mineral substitute materials can be used for preparing
a paste which can be injected directly into a fracture site. The
paste is injected into the void in the bone and, hardening, an
implant is obtained which conforms to the contours of the gap and
supports the cancellous bone. Both calcium sulphate and
hydroxylapatite materials have been extensively investigated as a
possible alternative to autogenous bone grafts to help restore
osseous defects of bone and fixation of bone fracture.
[0010] In this connection it is important that a complete stability
is obtained as quickly as possible during or after surgery in order
to prevent motions at site of healing. This especially applies to
fractures, but also when filling of a bone cavity or replacing bone
lost during tumor removal the healing is inhibited by movements and
the in-growth of new bone is prevented.
[0011] It is also of importance that the hardened material is so
similar in structure to the bone so that it can be gradually
resorbed by the body and replaced by new bone growth. This process
can be facilitated if the hardened cement is provided with pores,
which can transport nutrients and provide growth sites for new bone
formation.
[0012] M. Bohner et al. disclosed at the Sixth World Biomaterials
Congress Transactions (15-20/5 2000) a method to obtain an open
macroporous calcium phosphate block by using an emulsion of a
hydrophobic lipid (oil) in an aqueous calcium phosphate cement
paste or an emulsion of an aqueous calcium phosphate cement paste
in oil. After setting, the cement block was sintered at
1250.degree. C. for 4 hours. Likewise, CN 1193614 shows a porous
calcium phosphate bone cement for repairing human hard tissue. The
cement contains pore-forming agent which maybe a non-toxic
surfactant, or a non-toxic slightly soluble salt, acidic salt and
alkaline salt.
[0013] Studies have also been made on mixtures of the above
mentioned bone mineral substitute materials. In U.S. Pat. No.
4,619,655 is disclosed a bone mineral substitute material
comprising a mixture of Plaster of Paris, i.e. calcium sulphate
hemihydrate, and calcium phosphate ceramic particles, preferably
composed of hydroxylapatite, or tricalcium phosphate or mixtures
thereof. According to U.S. Pat. No. 4,619,655 tests show that when
alloplasts composed of 50/50 mixtures of hydroxylapatite/Plaster of
Paris were implanted into experimentally created defects in rat
mandible, the Plaster of Paris was completely resorbed within a few
weeks and replaced by connective tissue. The hydroxylapatite was
not resorbed and some particles were eventually completely
surrounded by bone. It was therefore concluded that the Plaster of
Paris acted as a scaffold for the incorporation of hydroxylapatite
into bone.
[0014] A recent study presented on the "Combined Orthopaedic
Research Societies Meeting", Sep. 28-30, 1998, Hamamatsu, Japan,
also shows additional tests relating to mixtures of Plaster of
Paris and hydroxylapatite. According to this study a combination of
hydroxylapatite particles and Plaster of Paris had a viscosity
which allowed an easy placement of the implant material and
prevented migration of hydroxylapatite particles into surrounding
tissues during and after implantation. The experiments showed that
Plaster of Paris was absorbed in relatively short time, was easily
manipulated with hydroxylapatite particles, and did not interfere
with the process of bone healing.
[0015] WO 9100252 shows a composition which is capable of hardening
in blood within about 10-45 min. The composition comprises
essentially calcium sulphate hemihydrate with small amounts of
calcium sulphate dihydrate. Organic and inorganic materials, such
as hydroxylapatite, can also be included in the composition. After
hardening, particles of hydroxylapatite are obtained within a
calcium sulphate cement. The calcium sulphate cement is dissolved
rapidly by aqueous body fluids within four weeks, leaving solid
particles of hydroxylapatite.
[0016] Likewise, such particles of hydroxylapatite within a calcium
sulphate cement are obtained by the method of WO 9117722. The
composition for use as an animal implant comprises calcium sulphate
hemihydrate, calcium phosphate, and sodium sulphate. The calcium
phosphate is hydroxylapatite and the sodium sulphate enables the
composition to be used in the presence of blood or other body
fluids.
SUMMARY OF THE INVENTION
[0017] The object of the invention is to provide an injectable
composition for a bone mineral substitute material with the
capability of being hardened in a body fluid in vivo, which hardens
during surgery with accompanying early control of fracture fragment
movement as well as provides a stable lasting implant over a year
with high mechanical strength, and which during this later period
presents a porous as well as irregular structure for bone in
growth.
[0018] A further object of the present invention is to provide such
an improved injectable bone mineral substitute for filling defects
in osteoporotic bone and for additional fracture fixation in
substantially cancellous bone which does not exhibit the drawbacks
of high viscosity at delivery and low fracture toughness.
[0019] Still another object of the invention is to provide an
injectable bone mineral substitute having excellent
biocompatibility, favorable biological and rheological properties.
The bone mineral substitute should also be biodegradable and be
possible to sterilize by radiation or gas without suffering a
significant deterioration in properties.
[0020] In order to achieve these objects the injectable composition
according to the invention has been given the characterizing
features of claim 1.
[0021] According to the invention a composition is provided which
comprises two types of bone cement materials, which both are
subjected to a hardening reaction in contact with water.
[0022] A cement of hardened calcium sulphate (gypsum) will remain
set in a dry environment. In a wet environment, such as in a Body
Simulated Solution, this material will immediately start to
disintegrate. Thus, an implanted material with reduced strength
will be obtained in the body. The solid material obtained will
start to degrade, eventually within 1-2 days.
[0023] On the other hand, in order to induce a setting (hardening)
reaction in a Body Simulated Solution or in a body with its blood,
saline can be used. By using saline a setting will be obtained
immediately under any conditions, but the implant obtained will
still degrade quite rapidly.
[0024] The second reaction, in which a calcium phosphate is
hardened (cemented) to a calcium phosphate cement in the presence
of water, will take longer time--about 18 h or more--in order to
set to a high strength material. During this period of time the
already set sulphate will confer an initial strength to the
implant, and when the setting reaction of tricalcium phosphate to a
high strength material is completed, a final strength will be
obtained, which lasts for months or years.
[0025] In this connection the term "calcium phosphate cement"
refers to the recognized definition (S. E. Gruninger, C. Siew, L. C
Chow, A. O'Young, N. K. Tsao, W. B. Brown, J. Dent. Res. 63 (1984)
200) of a reaction product of a powder or a mixture of powders
which--after mixing with water or an aqueous solution to a
paste--at a temperature around room temperature or body temperature
react with the formation of a precipitate, which contains crystals
of one or more calcium phosphates and which sets by the
entanglement of the crystals within the precipitate. Thus,
different calcium phosphate products (calcium phosphate cements)
can be obtained during the setting reaction in dependence on the
component(s) of the powders used for the paste inventive injectable
composition for a bone mineral substitute material.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The invention will now be explained in more detail,
reference being made to the accompanying drawings, in which
[0027] FIG. 1 shows the effects of a-tricalcium phosphate on
compressive strength;
[0028] FIG. 2 shows the effects of the content of calcium sulphate
dehydrate on the injection time; and
[0029] FIG. 3 shows the effects of the water content and the
content of calcium sulphate dehydrate on the setting time.
[0030] In order to accomplish an injectable bone mineral substitute
material having improved characteristics, tests were made with the
object to evaluate the effects of particle size, water content and
accelerator on the viscosity, setting time and porosity of the
injectable bone mineral substitute material of the invention.
[0031] The inventive injectable composition for a bone mineral
substitute material comprises a dry powder mixed with an aqueous
liquid. A main requirement on such a material is its setting time,
which should be within 5-12 minutes. Additionally, the viscosity of
the material should be adapted to render it injectable into the
bone for 1-5 minutes after the beginning of the mixing
procedure.
[0032] The evaluated materials comprised calcium sulphate
hemihydrate, also known as Plaster of Paris. It was found that the
addition of a small amount of finely ground already reacted calcium
sulphate dihydrate, CaSO.sub.42H.sub.2O, had a decisive impact on
the setting time and the injectable time of the bone mineral
substitute. Due to the addition of an accelerator the setting time
period was considerably shortened while the injectable time was
still long enough to make it possible to inject the material of the
invention into e.g. a bone cavity. It is assumed that other
accelerators and mixtures of accelerators may be used, e.g. starch,
mixtures of calcium sulphate. dihydrate and lignosulphate, calcium
sulphate dihydrates having composite coatings, etc.
[0033] Those reactions which forms hydroxylapatite, i.e.
precipitated hydroxylapatite (PHA) or calcium deficient
hydroxylapatite (CDHA), can be classified into three groups. The
first group consists of calcium phosphates, which are transformed
into hydroxylapatite by a hydrolysis process in an aqueous solution
(eq. 1-5).
5Ca
(H.sub.2PO.sub.4)H.sub.2O.fwdarw.Ca.sub.5(PO.sub.4).sub.3OH+7H.sub.3-
PO.sub.4+4H.sub.2O (1)
5CaHPO.sub.42H.sub.2O.fwdarw.Ca.sub.5(PO4)3OH+2H.sub.3PO.sub.4+9H.sub.2O
(2)
5Ca.sub.8H.sub.2(PO.sub.4).sub.65H.sub.2O.fwdarw.8Ca.sub.5(PO.sub.4).sub-
.3OH+6H.sub.3PO.sub.4+17H.sub.2O (3)
5Ca.sub.3(PO.sub.4).sub.2+3H.sub.2O
.fwdarw.3Ca.sub.5(PO.sub.4).sub.3OH+H.sub.3PO.sub.4 (4)
3Ca4(PO.sub.4).sub.2O
+3H.sub.2O.fwdarw.2Ca.sub.5(PO.sub.4).sub.3OH+Ca(OH).sub.2 (5)
[0034] Precipitated hydroxylapatite is the least soluble calcium
phosphate at pH over 4.2. This means that any other calcium
phosphate present in an aqueous solution at this pH range will tend
to dissolve, with the precipitation of PHA as a product. This
hydrolysis process (Ca(OH).sub.2-H.sub.3PO.sub.4-H.sub.2O) is very
slow due to a decrease in supersaturation as the reaction
proceeds.
[0035] The only calcium phosphate which can react via a hydrolysis
process to an apatite without the formation of sub-products is
a-tricalcium phosphate (eq. 6), and the apatite formed in this
reaction is a calcium deficient hydroxylapatite.
3.alpha.-Ca.sub.3
(PO.sub.4).sub.2+H.sub.2O.fwdarw.Ca.sub.9(HPO.sub.4)
(PO.sub.4).sub.5OH (6)
[0036] The second group of reactions to a hydroxylapatite, i.e.
precipitated hydroxylapatite (PHA) or calcium deficient
hydroxylapatite (CDHA), is the combinations between TTCP and other
calcium phosphates. TTCP is the only calcium phosphate with Ca/P
ratio above 1.67. Thus, this substance can be mixed with other
calcium phosphates with lower Ca/P ratio to obtain PHA or CDHA
without the formation of acids or bases as by-products.
Theoretically, any calcium phosphate more acid than PHA can react
directly with TTCP to form HA or CDHA according to the following
chemical reactions.
7Ca.sub.4(PO.sub.4).sub.2O+2Ca(H.sub.2PO.sub.4).sub.2H.sub.2O.fwdarw.6Ca-
.sub.5(PO.sub.4).sub.3OH+3H.sub.2O (7)
2Ca4(PO.sub.4).sub.2O+Ca(H.sub.2PO.sub.4).sub.2H.sub.20.fwdarw.<Ca.su-
b.9(HPO.sub.4) (PO.sub.4).sub.5OH+2H.sub.2O (8)
Ca.sub.4(PO.sub.4).sub.2O+CaHPO.sub.42H.sub.2O.fwdarw.Ca.sub.5(PO.sub.4)-
.sub.3OH+2H.sub.2O (9)
3Ca.sub.4(PO.sub.4).sub.2O
+6CaHPO.sub.42H.sub.2O.fwdarw.2Ca.sub.9(HPO.sub.4)
(PO.sub.4).sub.5OH+13H.sub.2O (10)
Ca.sub.4(PO.sub.4).sub.2O+CaHPO.sub.4.fwdarw.Ca.sub.5
(PO.sub.4).sub.3OH (11)
3Ca.sub.4(PO.sub.4).sub.2O+6CaHPO.sub.4.fwdarw.2Ca.sub.9(HPO.sub.4)
(PO.sub.4).sub.5OH +H.sub.2O (12)
3Ca.sub.4(PO.sub.4).sub.2O+Ca.sub.9H.sub.2(PO.sub.4).sub.65H.sub.2O.fwda-
rw.4Ca.sub.5(PO.sub.4).sub.3OH+4H.sub.2O (13)
3Ca.sub.4(PO.sub.4).sub.2O+3Ca.sub.9H.sub.2(PO.sub.4).sub.65H.sub.2O.fwd-
arw.4Ca.sub.9(HPO.sub.4) (PO.sub.4).sub.5OH+14H.sub.2O (14)
Ca4(PO.sub.4).sub.2O+2Ca.sub.3(PO.sub.4).sub.2+H.sub.2O.fwdarw.Ca.sub.5(-
PO.sub.4).sub.3OH (15)
[0037] In equations (7) and (8) DCPD is formed as an intermediate
reaction product, but with PHA or CDHA at the end of the reaction.
Reactions (13), (14), and (15) are all very slow. However, by using
the formulas (9)-(12) it is possible to produce a cement which sets
and hardens with time at room or body temperature and at a neutral
pH.
[0038] It is also possible to form PHA as the final hardened
product by using mixtures of calcium phosphates with a Ca/P ratio
of less than 1.67. This is accomplished by using additional calcium
sources, such as Ca(OH).sub.2 or CaCO.sub.3, instead of TTCP. One
example is the reaction .beta.-TCP+DCPD+CaCO.sub.3.fwdarw.PHA.
Initially formed crystals of PHA from a reaction between CDPD and
CaCO.sub.3 function as binders between .beta.-TCP particles. When
DCPD is consumed the reaction continues between the remaining
calcium carbonate and .beta.-TCP with the formation of PHA.
However, it seems that the latter process has a detrimental effect
on the mechanical strength of the cement.
[0039] It is preferred that the calcium phosphate with the
capability of being hardened to a calcium phosphate cement when
reacting with an aqueous liquid is tricalcium phosphate (TCP),
tetracalcium phosphate (TTCP), anhydrous dicalcium phosphate,
monocalcium phosphate monohydrate (MCPM), dicalcium phosphate
dihydrate (DCPD), or octocalcium phosphate (OCP). Preferably, the
calcium phosphate is a-tricalcium phosphate.
[0040] In order to confer an initial strength to a bone mineral
substitute material the calcium sulphate hemihydrate in the
composition according to the invention should comprise 2-80 wt %,
preferably 10-30 wt % of the dry powder to be mixed with an aqueous
liquid. Likewise, the calcium phosphate to be hardened to a calcium
phosphate cement should comprise 10-98 wt %, preferably 70-90 wt %
of the dry powder. In the composition, the aqueous liquid should
comprise between 0.1 and 2 ml, preferably between 0.5 and 1 ml per
gram powder.
[0041] By preferably using particulate reaction components in the
inventive composition, a high strength implant material will be
obtained initially. The fast setting calcium sulphate material will
be formed within a block of a slow setting material, i.e. the
calcium phosphate cement. Thus, when initial strength decreases the
second strength increases, and its final strength will be
maintained within the body. Pores, holes and cavities will
gradually be formed as the sulphate degrades, which acts like
lacuna, and the finally set and hardened implant of a high strength
material will look like a normal bone.
[0042] Both reactions in the inventive composition can be
controlled by including an accelerator or a retarder. By using seed
particles, the processes can be accelerated.
[0043] If such an accelerator is added, the calcium sulphate
hemihydrate will set rapidly, i.e. within 10 min. Particulate
calcium sulphate dihydrate is a suitable accelerator for this
reaction, the particle size being less than 1 mm. A more efficient
reaction is obtained if the particulate calcium sulphate dihydrate
has a particle size of less than 150 .mu.m, preferably less than
100 .mu.m, and most preferable less than 50 .mu.m. The particulate
calcium sulphate dehydrate should comprise between 0.1 and 10 wt %,
preferably between 0.1 and 2 wt % of the calcium sulphate
hemihydrate which is to react with an aqueous liquid. The
accelerator should be adapted so that a set material is obtained
within 15 min, preferably within 8 min, which has a threshold
strength of about 30 MPa in a clinical situation. Preferably, the
particulate calcium sulphate dihydrate is .alpha.-calcium sulphate
dehydrate.
[0044] The second reaction of a calcium phosphate to a calcium
phosphate cement sets slowly, but can be controlled to set within
18 h as a bone mineral substitute material with a strength of about
30 MPa. This can be accomplished by adding hardened particulate
calcium phosphate cement to the inventive composition. The hardened
calcium phosphate cement can be hydroxylapatite (HA), preferably
precipitated hydroxylapatite (PHA), tricalcium phosphate (TCP), or
a mixture thereof. It should have a Ca/P ratio between 1.5 and 2.
The particulate calcium phosphate cement should have a particle
size which is less than 20 .mu.m, preferably less than 10 .mu.m and
comprise between 0.1 and 10 wt %, preferably between 0.5 and 5 wt %
of the calcium phosphate which is to react with an aqueous
liquid.
[0045] The reaction of calcium phosphate to a calcium phosphate
cement can also be accelerated by a phosphate salt, for example
disodium hydrogen phosphate (Na.sub.2HPO.sub.4), which is dissolved
in the aqueous liquid. In this case, the accelerator should be
present in the aqueous liquid at concentrations of 0.1-10 wt %,
preferably 1-5 wt %.
[0046] The two types of accelerator for the reaction of calcium
phosphate to calcium phosphate cement can be used either separately
or in combination.
[0047] In the composition according to the invention the aqueous
liquid can be distilled water or a balanced salt solution, such as
PBS, PBSS, GBSS, EBSS, HBSS, or SBF.
[0048] The injectability of the composition according to the
invention can be improved in several ways. It has surprisingly been
shown that a pH reducing component can be added to the, inventive
composition, the injectability thereof being improved. Such a pH
reducing component is for example ascorbic acid or citric acid.
These acids are included in the sterile liquid or the sterile
powder of the composition in amounts of 0.1-5 wt %, preferably
0.5-2 wt %.
[0049] Another way to improve the injectability of the composition
is to add a biologically compatible oil. The concentration of the
oil should be between 0.1 and 5 wt %, preferably between 0.5 and 2
wt %. A suitable oil to be used in the inventive composition is
vitamin E. The oil can either be intermixed with the sterile powder
or included in the sterile liquid of the composition.
[0050] As stated above, the addition of a small amount of already
reacted calcium sulphate dihydrate had an effect on the injectable
time of the bone mineral substitute. Thus, by replacing some of the
non-reacted calcium sulphate hemihydrate with reacted calcium
sulphate dihydrate, the injectability of the composition could be
improved. As much as 95% of the hemihydrate can be replaced.
Preferably, 50-90% of the hemihydrate is replaced by the dihydrate,
most preferred 80-90%.
[0051] In order to further improve the bone mineral substitute
material obtained with the inventive composition it is possible to
further include additional substances, e.g. growth factors,
anti-cancer substances, antioxidants and/or antibiotics, etc.
Antibiotic containing bone cement is already known and it has been
shown that addition of antibiotics to synthetic hydroxylapatite and
cancellous bone releases said antibiotics in a concentration
sufficient for treating bone infections when said substances are
administered into the bone.
[0052] An efficient mixing system must be available in order to
prepare the composition according to the invention. The mixing can
take place in a conventional cement mixing system and the
composition is injected by means of a convenient delivery system.
The mixing container is preferably of that type which can suck the
aqueous component into the powder component (German Patent
4409610). This Prepack.TM. system is a closed mixing system for
delivery in combination with prepacked components in a flexible
foil bag. Other mixing devices can of course also be used, for
example two interconnected soft bags which can be adapted to a
delivering cylinder.
[0053] The formation of air bubbles in the composition, which can
interfere with the hardening reaction of the calcium sulphate
hemihydrate and result in a decreased initial mechanical strength
of the implanted material during surgery, can be prevented by
mixing the composition under conditions of subatmospheric pressure,
e.g. in vacuo. However, an atmospheric pressure can also be used.
Preferably, the powder component of the composition is sterilized
by means of radiation before it is mixed with the sterile liquid
component.
EXAMPLES
[0054] The invention will now be further described and illustrated
by, reference to the following examples. It should be noted,
however, that these examples should not be construed as limiting
the invention in any way.
Comparative Example 1
[0055] As a control test the injectable time and the setting time
of pure calcium sulphate hemihydrate were determined to be more
than 10 and 20 minutes, respectively.
Comparative Example 2
[0056] As a second control test the injectable time and the setting
time of a mixture of calcium sulphate hemihydrate, and
hydroxylapatite were also determined to be more than 10 and 20
minutes, respectively.
Comparative Example 3
[0057] The injectable time (IT) and the setting time (SI) were
studied for the first reaction of a calcium sulphate hemihydrate to
calcium sulphate dihydrate in the presence of a passive additive.
Twenty different mixtures of calcium sulphate hemihydrate,
hydroxylapatite (HA) and accelerator (Acc) were evaluated, which
had different ratios of hydroxylapatite and accelerator, see Table
3. The setting time was determined by a mechanical test. A metallic
rod having a weight of 23 g, a diameter of 10 mm and a length of 35
mm was dropped from a height of 35 mm. The time when the rod did
not leave any mark on the sample was registered as the setting
time.
TABLE-US-00003 TABLE 3 TEST CASO.sub.4 HA HA ACC IT SI NO. (G) (G)
(%) (%) (MIN) (MIN) 1 32 4 10 10 1.5 3.0 2 28 8 20 10 1.5 4.0 3 24
12 30 10 1.5 4.0 4 20 16 40 10 2.0 6.0 5 16 20 50 10 1.5 6.0 6 34 4
10 5 2.0 5.0 7 30 8 20 5 1.5 5.0 8 26 12 30 5 2.5 7.0 9 22 16 40 5
2.5 7.5 10 18 20 50 5 2.0 7.0 11 35 4 10 2.5 1.5 5.0 12 31 8 20 2.5
1.5 5.0 13 27 12 30 2.5 2.0 7.5 14 23 16 40 2.5 2.5 7.5 15 19 20 50
2.5 2.5 10.0 16 35.6 4 10 1 2.5 7.0 17 31.6 8 20 1 3.0 9.0 18 27.6
12 30 1 3.5 10.5 19 23.6 16 40 1 4.0 13.0 20 19.6 20 50 1 4.0
14.5
Example 1
[0058] Different bi-phasic injectable cements were produced, which
were based on a-tricalcium phosphate and .alpha.-calcium sulphate
hemihydrate.
[0059] The mechanical strength of each cement produced was
evaluated with time at 10 hours, 24 hours, 3 days, and 14 days
after mixing of the cement with water. The evaluation was performed
at the time periods given by means of a cylindrical specimen (d=6
mm, h=12 mm) that had been immersed in a physiological saline
solution of 37.degree. C. The results are shown in Table 4
below.
TABLE-US-00004 TABLE 4 Amount of Compressive Compressive
Compressive Compressive .alpha.-TCP strength 10 h strength 24 h
strength 3 d strength 14 d (wt %) (MPa) .+-. S.D. (MPa) .+-. S.D.
(MPa) .+-. S.D. (MPa) .+-. S.D. 0 11 3.63 7.64 1.41 12.99 2.66 9.66
3.2 20 1.01 0.39 1.69 0.49 3.99 0.35 5.36 0.33 40 0.68 0.25 5.08
1.66 8.82 1.2 9.82 1.86 60 3.58 1.02 5.1 0.91 15.73 5.24 14.13 1.42
80 5.31 1.03 10.72 0.69 21.8 3.41 23.92 3.06 100 6.24 1.48 22.37
6.34 37.99 4.74 33.98 10.37
Example 2
[0060] The compressive strength was further tested with reference
to a-TCP containing less than 20 wt % calcium sulphate hemihydrate
(CSH). (CSH was obtained from Bo Ehrlander A B, Gothenborg,
Sweden.)
[0061] The two powders were mixed together mechanically during 5
min. Then, the liquid was added to the powder at a liquid to powder
(L/P) ratio of 0.32 mlg.sup.-1. The liquid contained 2.5 wt %
Na.sub.2HPO.sub.4 as an accelerator.
[0062] Moulds were then filled and immersed in a saline solution
(0.9%,) at 37.degree. C. for 7 days. The results are shown in Table
5 below and in FIG. 1.
[0063] As seen in FIG. 1, the compressive strength was drastically
increased when the .alpha.-TCP content exceeded 80 wt %.
TABLE-US-00005 TABLE 5 Content of Compressive Standard No. of CSH
(wt %) strength (MPa) Deviation (MPa) samples tested 0 62.62 7.98 7
5 34.60 9.65 7 10 23.54 10.37 8 15 22.45 5.12 10
Example 3
[0064] During each of the two setting reactions, crystals are
formed when calcium sulphate hemihydrate and calcium phosphate,
respectively, react with water in the setting reactions. Initially,
crystal nuclei are created and the final crystal structure is then
formed by growth from the nuclei. By adding already formed crystals
of set material, the nucleation step in the setting process is
already completed, which will decrease the time needed to
crystallize the material and make it hard. The crystals will grow
directly from particles of added calcium sulphate dihydrate and
hydroxylapatite, respectively. Thus, these added particles of set
material will act as accelerators in the setting reactions.
[0065] The smaller size of accelerator particles added to the
material, the more efficient accelerating effect will be obtained
because the crystals will grow from the surface of the particles.
If the accelerator particles are small, then the surface of the
particles will be large per unit of weight.
[0066] When .alpha.-CaSO.sub.42H.sub.2O is used as an accelerator
it will be more efficient than .beta.-CaSO.sub.41/2H.sub.2O, when
.alpha.-CaSO.sub.21/2H.sub.20 is used as the main component of the
material. This could be explained by the crystal shape difference
between the two forms of the calcium sulphate. Since the crystals
are growing directly from the particle surface of the accelerator,
the reaction proceeds faster if the accelerator crystals have
exactly the same shape as the crystals that are forming from the
main component of the material.
Example 4
[0067] The effects of the content of calcium sulphate dihydrate on
the injection time is shown in FIG. 2. In this case the
liquid/powder (L/P) ratio is 0.4 ml/g. The limit of injection time
was defined when the load reached N, which is comparable to the
highest force by hand at which injection was possible.
Example 5
[0068] The effects of the water content and the content of calcium
sulphate dihydrate on the setting time is shown in FIG. 3, wherein
L/P is the liquid-powder ratio (ml/g). The setting time was
measured by using Gillmore Needles according to ASTM Standard
C266.
Example 6
[0069] In the inventive composition, the form of the calcium
sulphate hemihydrate is of importance. .alpha.-Calcium sulphate
hemihydrate (.alpha.-CaSO.sub.41/2H.sub.2O) is advantageous to use
because of its mechanical strength. .alpha.-CaSO.sub.41/2H.sub.2O
has a compressive strength of 40.4 MPa compared with 14 MPa for
.beta.-.alpha.-CaSO.sub.41/2H.sub.2O.
Example 7
[0070] Biodegradation of the Calcium Sulphate with Hydroxylapatite
bone substitute in vitro and in vivo.
[0071] The degradation rate of calcium sulphate with 40 wt %
hydroxylapatite was investigated. The material was placed in a
Simulated Body Fluid as well as muscle pockets in rats. The
mechanical strength and size of the block obtained were
investigated with time as a biodegradation index.
[0072] Mechanical testing
[0073] Compressive strength testing was performed using an MTS and
Instron 8511.20 testing equipment. After harvesting the materials,
the samples were directly placed between self-levelling platens and
compressed at 1 mm min.sup.-1 until failure at room
temperature.
[0074] Volume measurements
[0075] After the material harvesting, a caliper measured the volume
of the block of material.
[0076] In vitro Study
[0077] Cements of calcium sulphate or calcium sulphate with
hydroxylapatite were prepared by mixing with distilled water at L/P
ratio of 0.25 ml/g. After mixing the cement was injected into a
PFTE mould and allowed to set. The samples were 4 mm in diameter
and 8 mm in length. Six cylindrical samples were placed in a
Simulated Body Fluid, and the liquid was changed every day. After
one week the samples were directly placed between self-levelling
platens and subjected to compressive strength testing until failure
at room temperature.
[0078] In vivo Study
[0079] Materials preparation
[0080] Calcium sulphate hemihydrate (CaSO.sub.41/2H.sub.2O) was
mixed with 40 wt % hydroxylapatite powder
(Ca.sub.10(PO.sub.4).sub.6 (OH).sub.2; HA). The mixture of POP-HA
was sintered and quenched in air. An accelerator (a calcium
sulphate) was added at 0.4 wt % to the POP-HA, and the dry powder
material was sterilized by gamma-irradiation.
[0081] A cement was prepared by mixing the powder with distilled
water at a L/P ratio of 0.25 ml/g. Materials were prepared, which
contained calcium sulphate or calcium sulphate+hydroxylapatite.
After mixing, the cement was injected into a PFTE mould and allowed
to set. The samples were cylindrical with diameter of 4 mm and
height of 8 mm. Once set, the samples are inserted into muscle
pockets of rats.
[0082] Animals
[0083] ague-Dawley rats weighing around 200 g were used and kept in
animal facilities for 1 week before use. The animals were fed a
standard laboratory diet. All rats were anesthetized with
peritoneal injections of 0.5-0.6 ml of a solution containing 1 ml
pentobarbital (60 mg/ml), 2 ml diazepam (5 mg/ml), and 1 ml saline
(0.15 M). The implants were inserted in muscles of the rats. Nine
rats were used for each period studied. The rats were killed by a
peritoneal injection of an overdose of pentobarbital at 1 or 4
weeks after implantation.
[0084] Results
[0085] After one week of incubation the mechanical strength was
recorded of the cylindrical samples placed in the Simulated Body
Fluid or muscles pockets in rats, respectively. The mechanical
strength of the materials had decreased from 35 Mpa to about 5 Mpa
both in vitro as well as in vivo. The volume of remaining block was
only 1/3 to 1/10 of the original block volume (Table 5).
[0086] After 4 weeks of incubation, the mechanical strength of the
materials had totally disappeared, and the rods of calcium sulphate
were almost completely absorbed. The calcium sulphate with
hydroxylapatite was still present but totally deformed, and the
material was surrounded by normal soft tissue. The tissue also
penetrated into the materials. Furthermore, the mass of remaining
material was larger than the original block implanted.
[0087] Table 6 below shows the volume of remaining cylinder
material (Mean .+-.SE) in rat muscles after an incubation of 1 or 4
weeks. The original volume of the cylinder material was 100
mm.sup.3. Statistic analysis was performed by using the one way
ANOVA method and Student's t-test. All results obtained exhibited a
high statistical significance (p<0.0001).
TABLE-US-00006 TABLE 6 1 week incubation 4 weeks incubation No. of
Volume No. of Volume Material samples (mm.sup.3) samples (mm.sup.3)
PoP 9 31.7 .+-. 3.1 9 1.9 .+-. 1.5 PoP t HA 9 6.1 .+-. 1.5 8 159.4
.+-. 21.7 PoP + HA + Vitamin E 8 9.1 .+-. 2.0 8 196.0 .+-. 17.9
[0088] The implanted material comprising calcium sulphate and
hydroxylapatite was rapidly degraded within one week in both
Simulated Body Fluid and in rats. The rate of degradation was the
same in Simulated Body Fluid or muscles pockets, indicating that
only one method is needed in order to demonstrate the degradation
rate.
[0089] In conclusion, tests of the combined sulphate and phosphate
material exhibit biodegradation in vitro and in vivo as well as
hardening of both components with good results with reference to
injectability and setting.
* * * * *