MXPA97006809A - Controlled dissolution pella cal contienesulfato - Google Patents

Abstract

The present invention relates to the controlled release of calcium sulfate as well as the controlled release of an additive to a calcium sulfate matrix, such as drugs or pesticides, controlled release is achieved by a pellet comprising calcium sulfate; Pellet is prepared by the process comprising mixing the powder consisting essentially of alpha-calcium sulfate hemihydrate, a solution comprising water and, optionally, an additive and a powder consisting essentially of a beta-calcium sulfate hemihydrate to form a mixing and transforming into a pellet, wherein said alpha-calcium sulfate hemihydrate and beta-calcium sulfate hemihydrate powders have specified properties, such as surface areas, densities, average particle sizes and purities of BET; of the calcium sulfate pellet is controlled by varying the weight ratio of the beta-calcium sulfate powder hemihydrate The alpha-calcium sulfate powder hemihydrated from 0 to about 3, the invention also provides a method for releasing medicament in vivo by implanting a pellet prepared with medicament to a human or animal.

Description

CONTROLLED DISSOLUTION HAIR CONTAINING COLOC SULFATE BACKGROUND OF THE INVENTION This invention relates to the controlled release of a calcium sulfate matrix, as well as to the controlled release of a matrix additive such as a medically or a pesticide. The controlled release of the drug in vivo is the subject of many investigations. Several methods and releasing agents have been suggested, tested and marketed. Calcium sulfate has been used as a filler for bone cavities since it is adsorbed and spontaneously replaced by bone. Calcium sulfate, formed from the herbicide, has been used as a controlled release agent only for the filling of bone cavities and in combination with additives such as drugs and pesticides. As a vehicle for medications, it has been useful in vivo, because it is biocompatible and is progressively reabsorbed by the body, thus eliminating the need for secondary surgical procedures. An application for a controlled release agent of calcium sulfate is the local assortment of drugs in vivo. The ideal characteristics of a local medication assortment system are (1) biodegradability, (2) biocornpatibility, (3) prolonged pharmaceutical release (a minimum of 4 to 6 weeks), (4) reproduction capacity, (5) far akinetic predictable and (6) controllability. Applications include the assortment of antibiotics to bone infections, chemotherapy, where the surgery can be either inpractic or irnp > possible, and the assortment of growth factors and analgesics. The currently acceptable methods of drug assortment are somewhat limited and predictable. Intravenous antibiotic therapy is the most effective route, but requires high levels of drug in the serum to obtain adequately high levels at the site of infection. This can lead to serious complications in organs such as the kidneys and the liver. The oral assortment of antibiotics is subjected to the unpredictable nature of gastrointestinal absorption to obtain the required amounts of the drug where it is needed. The assortment by means of implantable pumps is another method, but the pumps are invasive, they must be removed, and the body can react to the presence of a foreign body at the site of the infection. The most popular current method of localized assortment is the use of polymethyl methacrylate (bone cement) impregnated with antibiotics. This method allows to obtain high levels of drug in the tissue without poisoning the entire system. However, it also has its limitations, since bone cement is a very dense material and is only capable of supplying a limited amount of drug for a short time. Fidemás of this, the bone cement is not biodegradable, therefore it needs to be surgically removed at a later date, and acts as a foreign body in an infected site, leading to other complications. Therefore, the use of calcium sulfate with its properties of biocopatability and progressive reabsorption as a vehicle for drugs would be highly desirable. However, the disadvantages of the use of calcium sulfate as a vehicle, whether in vivo or not, are its rapid rate of dissolution and the inability to control the rate of dissolution and, consequently, the rate of release of any additive. Various ways have been tried to control the speed, for example varying the density or mass of the calcium sulfate matrix, but these methods have not been very effective. It is therefore an object of the present invention to provide controlled release of calcium sulfate. It is also another object to provide controlled release of an additive such as a medicament or a pesticide that can be mixed in a calcium sulfate matrix. A further object is a method for preparing a calcium sulfate pellet with or without an additive.

BRIEF DESCRIPTION OF THE INVENTION The objects of the present invention are provided by a pellet having a controllable dissolution rate, wherein said pellet comprises calcium sulfate and is prepared by the process comprising: (a) mixing powder consisting essentially of alpha-calcium sulfate I have hydrated and, optionally, powder consisting essentially of beta-calcium sulfate herni with a solution comprising water to form a mixture, and (b) forming said mixture into a pellet, wherein said powder consisting essentially of sodium sulfate Alpha-calcium hernihydrate has a purity of more than 98% by weight of calcium sulfate hemihydrate, a BET surface area on the scale of from about 0.4 m 2 / g to about 0.9 m 2 / g, a density on the scale of about 2.75 to about 2.80 g / cm3, an average particle size of about 16 μrn to about 22 μrn, and wherein 90-95% by weight of the powder consists essentially of alpha-calcium sulfate hernihydrate with a particle size distribution of about 1 μ to about 45 μ, wherein said powder consists essentially of beta-calcium sulfate hemihydrate having a purity of more than 98% by weight of sulphate of calcium hemihydrate, a BET surface area on the scale of from about 4.5 m2 / g to about 7.5 m2 / g, a density on the scale of from about 2.5 g / cm3 to about 2.6 g / cm3 and an average particle size in the scale from about 10 μ to about 15 μm, and wherein the rate of dissolution is controlled by varying the weight ratio of the powder consisting essentially of beta-calcium sulfate hemihydrate to the powder consisting essentially of alpha-calcium sulfate hemihydrate from 0 to approximately 3. The alpha- and beta-calcium sulfate herbal hydrate powders consist essentially of the alpha and beta crystal forms, respectively. tea. Impurities such as calcium sulfate dihydrate may be present, but are not important for controlling the rate of dissolution of the pellet. The preferred scale for the surface area of the alpha-calcium sulfate hydride powder is from about 0.4 rn2 / g to about 0.7 rn2 / g, and for the surface area of the beta-calcium sulfate hemihydrate powder, from about 5 m2 / ga approximately 6 m2 / g. The preferred average particle size for the alpha-calcium sulfate hemihydrate powder is from about 18 μm to about 22 μm, and for the beta-calcium sulfate hemihydrate powder from about 13 μm to about 14 μm. The preferred weight ratio of the berta-calcium sulfate hemihydrate powder to the alpha-calcium sulfate hemihydrate powder is in the range of from about 0 to about 0.33 for the controlled release of most drugs. More limited scales of this relationship are also contemplated, e.g., 0 to approximately 0.11, 0 to approximately 0.05 and 0 to approximately 0.02. When used to carry growth factors, the weight ratio of the beta-calcium sulfate hemihydrate powder to the alpha-calcium sulfate hemihydrate powder can vary up to about 3: 1. The invention also provides a pellet comprising additives such as medicaments or pesticides and a method for dispensing medicament in vivo by preparing the pellet with medicament and implanting it into a human or an animal. These pellets are promising as controlled release matrices where other preparations have not been successful.

BRIEF DESCRIPTION OF THE FIGURES The advantages of the present invention will become apparent after reading the following detailed description and referring to the accompanying drawings, in which: Figure 1 shows the daily weight of the calcium sulfate pellet ("CS") solution with the time for several consistencies of mixing the calcium sulfate powder hemihydrate ("CSH"); Figure 2 shows the fractional loss of wet weight for the dissolution of the CS pellet over time; Figure 3 shows the weight of the daily solution of the CS pellet; Figure 4 shows the dissolution speed of the CS vs. CS pellet. the empty sample fraction; Figure 5 shows the comparison of dissolution rates of the CS pellet in saline; Figure 6 shows the comparison of the cylindrical and cubic pellets; Figure 7 shows the average daily weight of pellets in normal saline at 37 ° C; Figure 8 shows the average loss of material per day for CS pellets in normal saline at 37 ° C; Figure 9 shows the dissolution of cumulative percentage material in normal saline at 37 ° C; Figure 10 shows a comparison between the dissolution rates of the materials in examples 1 and 2; Figure 11 shows the daily levels of tobramycin in serum and tissue; Figure 12 shows the average levels of tobramycin in tissue for all implants; Figure 13 shows average serum tobramycin levels for all implants; Figure 14 shows the initial levels of tobramycin in the tissue of the implants vs. the molted; Figure 15 shows steady-state levels of tobramycin in tissue of the implants vs. the moldings; Figure 16 shows the initial levels of tobramycin in the serum of the implants vs. the moldings; Figure 17 shows steady-state levels of tobramycin in the serum of the implants vs. the mills; Figure 18 shows the surface area of the implant vs. weather; and Figure 19 shows a comparison of the dissolution in vir.ro vs. in vivo of pellets prepared with alpha-calcium sulfate powder hemihydrate.DETAILED DESCRIPTION OF THE INVENTION The calcium sulfate pellet of the present invention can be used alone or as a matrix for an additive to thereby control the release rate of said matrix and / or calcium sulfate additive. The pellet is prepared by mixing alpha-calcium sulfate powder hemihydrate and, optionally, beta-calcium sulphate hemihydrate powder in a solution consisting essentially of water and then shaping it by molding or applying pressure. The solution may also comprise sodium chloride, that is, it may be a saline solution. The weight ratio of water to calcium sulfate powder hemihydrate is in the range of from about 0.22 to about 1, preferably in the range from about 0.27 to about 0.30. The consistency of a calcium sulfate hemihydrate powder (ie, solution in mL / gram of calcium sulfate hemihydrate) is proportional to its surface area and depends on the morphology of the crystal. Powders with a greater surface area have a higher water demand and will not mix or set at lower consistencies. After contact of the water or saline with the alpha- or beta-calcium sulfate powder herni hydrate, the hernihydrate is converted to the dihydrate. Preferred calcium sulfate powder includes Capset® powder (available from LifeCore of Chaska, Minnesota, E.U.A.), which is composed of alpha-calcium sulfate hemihydrate; Hapset® powder (also available from LifeCore) which is composed of alpha-calcium sulfate hemihydrate mixed with granulated hydrated calcium phosphate; and OsteoSet "(available from Uright Medical Technology, Inc. of Arlington, Tennessee, USA), which is composed of alpha-calcium sulfate hernihydrate If additives are desired, they can be mixed with calcium sulfate powder before mixing. with a solution comprising water or dissolving them in the solution, and subsequently impregnated in the calcium sulfate powder.The additive comprises from 0 to about 25% by weight of the pellet, preferably about 2% by weight to about 10% by weight. weight, most preferably about 2% by weight to about 5% by weight Examples of additives that can be mixed in the calcium sulfate matrix are drugs or pesticides Examples of drugs that can be mixed with the calcium sulfate matrix are antibiotics , chemotherapeutic agents, growth factors and analgesics Examples of antibiotics are tetracycline hydrochloride, vanco icine, cephalosporins and inoglycosides t ales such as tobramycin and gentamicin. Examples of quiniotherapeutic agents are cis-platinum, ifosfamide, rnetotrexate and doxorubicin hydrochloride (Adriamycin®). Examples of growth factors are the beta factor of growth transformation (TGF-Beta), bone morphogenic protein (BMP), basic fibroblast growth factor, platelet-derived growth factor and other polypeptide growth factors. Examples of analgesics are anesthetics such as lidocaine hydrochloride (Xilocaine *), bipivacaine hydrochloride (Marcaine *) and non-steroidal anti-inflammatory drugs such as ketorolac tromethamine (Toradol) .The performance of pellets manufactured by molding or compression have profiles of release and quite comparable in vivo solution speeds.This leads to a great versatility in the ability of the material to be adapted to the needs of the particular application.The material can be pre-formed for ease of use or mixed as needed. required to meet a speed or release profile specified by the surgeon in the operating room.

The following examples will show that pellets prepared from the alpha-calcium sulfate powder hernihydrate with or without beta-calcium sulfate powder hemihydrate, have been shown to be a controlled release system which is an effective assortment medium, both in vivo and in vitro. They will also show that the system is safe to use in vivo and effective to deliver medication locally and in a controlled manner. The high levels of antibiotic in the tissue were obtainable during an extended period while maintaining a safe and low systematic effect. The other advantages of reproductive capacity, biodegradability and biocornpatibility make this an extremely attractive in vivo system. Since the pellets are resorbable, the need for additional invasive surgery to remove the material is virtually eliminated, and theoretically all of the drug is available for application.

EXAMPLE 1 An experiment was carried out to show that a calcium sulfate pellet prepared using alpha-con sulfate powder or without beta-calcium hemihydrate having specific properties can decrease the dissolution rate of a pellet. Calcium sulfate ("CS") pellets were prepared using alpha-calcium sulfate hemihydrate powder at 27 and 37 rnL of normal saline per 100 g of calcium sulfate hemihydrate powder, and beta-calcium sulfate powder hemihydrate mixed at 65, 80 and 100 L of normal saline per 100 g of calcium sulfate powder hemihydrate. The mixture was allowed to dehumidify for 60 seconds and then mix rapidly with a spatula for 30 seconds. The suspension was emptied in cylindrical molds of 2 crn of diameter x 2 crn in height and the setting of Vicat of 300 g was measured in the rest of the suspension. The setting of Vicat is a measure of the time that makes a mixture harden so that it can withstand a specific mass placed on a needle, eg, 300 g. The samples were allowed to hydrate approximately 10 minutes beyond the setting of Vicat and then they were demoulded and weighed. The samples were dried in an oven at 45 ° C until a constant weight was obtained. Each sample was operated in triplicate. The average initial wet and dry weights and the Vicat setting times (300 g) of the samples are given in Table 1.

TABLE 1 Wet and dry weights of the sample and Vicat setting times The dissolution rates of the pellets were tested by placing them in a saline solution and removing them from the solution periodically to weigh them. The test solution was a normal saline solution prepared by adding sodium chloride to deionized water. This saline was stirred and heated to about 37.8 ° C on a heater / stir plate. Two hundred mL of the heated saline solution was placed in a polyethylene bottle and a cylindrical pellet was added in such a way that the pellet rested on its curved side and not on the flat surface. The bottles were labeled and placed in a water bath and kept at 37 ° C. Once a day, at intervals of approximately 24 hours (+/- 90 minutes), the pellets were removed from the bottles, the excess moisture was removed on a paper towel, and the weights were recorded to the nearest milligram. The saline solution used was discarded and fresh saline prepared as above was placed in each bottle. The pellets were returned to the bottles and the bottles to the bathroom. Figure 1 shows the average daily weight of each sample. Figure 2 shows the average cumulative fractional weight loss (from the initial wet weight) and shows that the solution is essentially linear with time. The exceptions to linear character in weight loss occur on the first day and when a large fraction of the samples has dissolved. The substantial weight loss on the first day may be due to the fact that the samples were dried to a constant weight before being submerged in the saline solution, thus generating an outer pellet surface area in some larger form. The decrease in the speed of weight loss is particularly evident in the IDO consistency samples in the last 20% of the solution. Figure 3 shows the average daily weight loss for the samples of each consistency. It is clear that after day 1, the loss in weight is quite constant (however, noticing again the exception, particularly of the samples of consistency 100 of the last periods). Table 2 shows the average daily weight loss and the normal deviation of the sample for the samples of each consistency from day 2 to day 18. From Table 2, it is apparent that the samples with the highest consistency had a loss of greater absolute average daily weight, as well as a greater average daily fractional weight loss, as observed in figure 2. The deviations appear to be marginally greater in the higher consistencies.

TABLE 2 Average daily weight loss The solubility of calcium sulfate dihydrate ("CSD") is approximately 0.0140 M on the temperature scale of interest. This would correspond to 0.482 g of CSD per 200 mL of water. It has been found that at 25 ° C, the solubility of CSD increases by 30% compared to pure water. This would give a solubility of approximately 0.627 g per 200 L of saline. The measured decrease in sample weights was substantially less than this figure, except on the first day, where the largest loss was in the 65 consistency samples, an average of 0.744 g. It should be noted that this weight loss contains a water-free component as well as a CSD component. The solubilities mentioned above are not corrected for temperature. The results suggest that saturation effects did not intervene in the dissolution rate observed. The rate of dissolution is best observed from the slopes in Figure 2. The intersections are somewhat distant from zero due to the large dissolution observed during the first day. The linear regression analysis of the fractional data of weight loss from the first 18 days of dissolution is given in Table 3.

TABLE 3 Linear regression values of the slopes and R2 of Figure 2 The increase in the dissolution rate with consistency suggests the covariation of the effective surface area. This is hardly a surprising result. However, the linear nature of these results suggests, in the reasonably assumed absence of saturation effects, that the effective surface area of the samples remains constant, even after well over half of the sample has dissolved. This conclusion suggests in turn that the rate of dissolution is controlled by the diffusion rate in saline at 37 ° C. Only after approximately 80% of the sample has dissolved, the actual effective surface area begins to reduce the rate of dissolution. The relationship between the absolute dissolution rate in g / days versus the empty fraction is shown graphically in Figure 4. (The empty fraction is calculated by subtracting from 1 the ratio of the average density of the dry sample to the theoretical density of the CSD). In a related experiment, the dissolution of CSD samples in both water and saline prepared from industrial gypsums comprised of alpha-calcium sulfate hemihydrate and beta-calcium sulfate hemihydrate at various consistencies was observed. Consistencies greater than 40 rnL / 100 g of CSH were prepared with beta-calcium sulfate hemihydrate and consistencies of less than 400 mL / 100 g of CSH with alpha-calcium sulfate hemihydrate. The samples were 5.08 cm cubes. Six liters of 0.85% saline solution were used and the temperature was controlled at 23.9 ° C. Figure 5 compares the dissolution rate of the sample in saline co or a function of the consistency of the mixture for the two experiments. If, as previously suggested, diffusion is the event that controls the speed, then the observed differences could be due to the higher temperature used in the present study. However, the ratio of the coarse surface area of the sample to the volume is substantially greater in the straight circular cylinders than in the cubes. This can also increase the rate of fractional dissolution. If the data in the two series of experiments are normalized to the respective dissolution rates of the 100 consistency samples, the internal concordance of the results is apparent. These normalized data are shown in Figure 6, accompanied by lines adjusted by least squares. The data shows that the absolute and relative weight loss rate depends on the consistency of the CSH mixture - the greater the consistency, the higher the speed. Therefore, the effective surface area seems to be the key p > for the speed of relative dissolution. The linearity of the solution over time suggests that the effective surface area is independent of the sample size until the sample has largely disappeared, and that the diffusion of the solid dissolved in solution controls the speed in the experimental protocol used.

EXAMPLE 2 An experiment was conducted to determine the in vitro effect of the consistency of the mixture on the rate of resorption under conditions that approximate the body environment. The temperature of the samples was maintained at the temperature of the human body. The water had a normal salt concentration. Calcium sulfate ("CS") pellets were prepared with different mixtures of alpha-calcium sulfate powder ("-CSH"), hernihydrate, and beta-calcium sulfate ("β-CSH") hemihydrate, and sulfate powder calcium dihydrate ("CSD"). The powders were mixed with normal saline or deionized water, allowed to soak for 60 seconds and mixed vigorously to form a suspension. Then, a spoonful of the suspension was poured into the plastic mold and the material was allowed to harden to form cylindrical pellets 4 c in height by 1.2 cm in diameter. The rest of the suspension was used to measure the setting time of vicat of the mixed material by hand (300 g). The powder and the solution with which the samples were prepared are the following: Approximately 10 minutes after the setting time of Vicat, the mold was opened and the pellets were removed. One hour after rehydration, the pellets were placed in an oven at 45 ° C until a constant weight was reached. The pellets were then measured in terms of their dimensions with metric calibrators and the weights were recorded. The dissolution rates of the pellets were tested by placing them in a saline solution and periodically extracting them from the solution to be weighed in accordance with the method described in Example 1. Table 4 details the dry weight, height, diameter and density of the pellets. Table 5 lists the average daily weight, weight loss and the cumulative percentage of weight loss. The values in Table 5 are shown in Figures 7, 8 and 9.

TABLE 4 Dry pellet data TABLE 5 Data averaged for daily weight, weight loss and aquiulative percentage of weight loss TABLE 5 (continued) Two water baths were required to keep all the pellets at 37 ° C. During day 11 of the experiment, a malfunction in a bath was observed that caused an increase in temperature up to 50 ° C. The result was an increase in the dissolution of the material, as shown in figures 7, 8 and 9 for samples E and F. The problem was solved and the pellets returned to the original dissolution rates, as can be observed by the slopes in the figures. Interruptions are observed where the materials were allowed to rest for weekly periods without changing the solutions near the end of the study. Again, the slopes and speeds returned to the same "rhythm" as they had originated after the salt solutions were changed. As was the case in Example 1, the dissolution of the material was linear through the first 80% weight loss of each of the pellets, and the rates tended to decrease a little in at least 20% of the dissolution . Table 6 shows the daily average of weight loss and the linear regression of the percentage of weight loss for the first 80% dissolution of each of the six types of pellets. This further shows how the pellets of the present invention prepared using alpha-CSH with "or without beta-CSH (samples B, C and D) have higher dissolution profiles than pellets prepared with beta-CSH (sample A) or with alpha -CSH and CSD (samples E and F) TABLE 6 Daily average of weight loss and standard deviation, loss rate and correlation coefficient for samples A to F through 80% dissolution Figure 10 further compares the results of this study with those of Example 1, where cylindrical castings were evaluated for dissolution rates in 0.9% saline at 37 ° C. The only significant differences between the two studies, are the hernihydrate bases evaluated and the surface area relationships with respect to the volume of the cylindrical castings. Clearly, the slopes are the same and, in effect, the correlation coefficient of the two data series is 1.00. All the formulations have shown consistent and predictable behavior throughout the experiment. The results suggest that pellets prepared using alpha-CSH materials with and without beta-CSH can be designated as usual to control the rate of dissolution, and thus the rate of release of any additive, in vivo or in vitro, and that in vivo resorption can be adapted to meet a specific demand or application by the particular selection of the medical material and the consistency of use.

EXAMPLE 3 In vitro study: tetracycline hydrochloride A 1 gram pellet was prepared by the procedure of Example 1, except that the calcium sulfate hemihydrate powder was only alpha and contained medicament, and a solution of pure water was used instead of saline . The alpha-calcium sulfate hernihydrate powder (800 mg) was dry mixed with approximately 200 rng tetracycline hydrochloride. The dry mixture was then added to 0.25 mL of pure water and formed into a pellet by applying pressure (approximately 3.515 kg / crn2 for approximately 5 minutes). The pellet was composed of 80% by weight of alpha-calcium sulfate powder and ihydrated and 20% by weight of tetracycline hydrochloride. The pellet was placed in 120 L of deionized water in a plastic jar suspended in a 37 ° C water bath. The water changed periodically. When the water was changed, the pH was measured and aliquots were made for visible / ultraviolet light absorbance spectroscopy to determine the amount of tetracycline in solution. Soaking time of the aliquots, cumulative soaking time, pH, milligrams of tetracycline, the percentage of the original tetracycline, and the cumulative percentage of tetracycline, are reported in Table 7. The maximum absorbance value at 357 manometers were used to determine the tetracycline concentration by comparison with standards. The variation in pH adds certain uncertainty to the percentages presented.

TABLE 7 In vivo release of tetracycline hydrochloride These results indicate that a sustained release of a drug is achieved in an area localized from a calcium sulfate matrix over a prolonged period.

EXAMPLE 4 In vivo study: tobramycin sulfate in rats 14 pellets were prepared by the procedure of Example 3, except that the drug was tobramycin sulfate. In table 8 the physical dimensions, weights and densities of the individual pellets are given. Reproducibility, as observed in standard deviations, seems to be acceptable for an experimental procedure.

TABLE 8 TABLE 8 (continued) Pellets were implanted in 3 Sprague Dowley rats and tobrannicin levels in serum and tissues were monitored. The results of the experiment are presented in Figure 11. The duration of the release is well coupled to the needs of this type of medication. The low serum levels (serum) and the high local concentration (tissue) make this a particularly satisfactmethod of antibiotic release in cases of surgical repair or removal of tissue, or as an adjunct to implant procedures. The results of Examples 3 and 4 show the ability to form calcium sulfate pellets for sustained and controlled release of tetracycline hydrochloride and tobramycin sulfate using alpha-calcium sulfate hemihydrate powder. These results indicate that a sustained release of a drug in an area localized from a calcium sulfate matrix is achieved, while maintaining a very low level of medication in the blood over a prolonged period.

EXAMPLE 5 In vivo study: compressed versus molded implants A study was carried out to see if the release rate depended on the preparation method of the pellets.

The pellets were prepared by compression or molding methods at a consistency of 37 ml of water / 100 g of alpha-calcium sulfate hemihydrate powder. Compressed Pellets: Compressed pellets were produced starting with a dry mixture of 83.4656 grams of alpha-calcium sulfate hemihydrate powder, 2.0425 grams of tobramycin sulfate and 1.0052 grams of fresh ground calcium sulfate dihydrate mixed thoroughly for 10 minutes. A punch and pellet die were used to form the pellets by adding 1.75 grams of the powder mixture to 472 uL of sterile saline (measured with a variable volume pipette Model V200TE, Ulster Scientific, Inc.), stirring to a uniform consistency and allowing the mixture to settle for 5 minutes. A Carver laboratory compressor (Model M) was then used to compress the pellets @ 3.515 kg / cm2 until the mixture hardened (5 minutes) and could be expelled from the die. 30 minutes after the initial hydration, the pellets were placed in an oven at 45 ° C and dried at constant weight. The final pellets had average cylindrical dimensions of 9.63 ml in height and 11.15 mm in diameter, with a load of 2 wt% of tobramycin (approximately 40 g). In this way, a total of 30 pellets were manufactured for the study. Then, the implants were individually weighed, measured and packaged to be sterilized secondarily by 2.5 regimens of gamma irradiation. Molded pellets: It was determined by temperature increase studies that the material would be hydrated substantially at 30 minutes (Vicat setting to about 6 minutes) using the mixing techniques and consistency described below. The molded implants were produced in the operating room at the time of the animal experimentation. For this procedure, packages containing 50.0 g of alpha-calcium sulfate hemihydrate powder and bottles with 1.20 g of tobramycin sulfate were provided from the same corresponding batches as were used for the compressed implants. These materials were sterilized in their individual packages by exposure to 2.5 gamma irradiation screens. The molding of the pellets was carried out as follows. A bottle with 1.20 grams of water-soluble tobrarnicine sulfate was mixed with 15 L of sterile water. A 50.0 gram pack of alpha-calcium sulfate hemihydrate powder was then added to the solution and mixed by hand in a small mixing bowl until a uniform smooth consistency was achieved. This mixture was then placed in the mold and allowed to rest for 20 minutes until the mold could be separated and the implants removed. Three implants were obtained by this procedure which produced a load of 2% by weight of tobramycin sulphate (approximately 170 rnb per implant). Table 9 shows results of this test for 3 pellets immediately after they were demolded (approximately 20 minutes after the mixing began).

TABLE 9 Properties of molded pellets immediately after removal from the mold The dicks were then dried at 45 ° C until a constant weight was obtained, and the results are shown in Table 10.

TABLE 10 Pellets molded after drying at constant weight Tables 9 and 10 show a uniform and consistent product. An animal study with a main test was conducted according to the following protocol: 1) Six pellets of hybrid breed (approximately 25 kg each) were implanted with pellets prepared with alpha-calcium sulfate, hernihydrate powder and tobramycin: a) Three dogs that used four compressed pellets, previously manufactured for each dog. b) Three dogs that used a molded pellet in the operating room as described above. 2) Samples of both tissue and serum from the animals were obtained in terms of tobramycin levels at hours 1, 3 and 24 on days 2, 3, 5, 7, 14, 21, 28, 35 and 42. 3) X-rays were taken on days 0 (postoperatively), 11, 28 and 35 .. 4) On day 42, the experiment was completed to assess the local response of the tissue to the implants. Each procedure required approximately 30-40 minutes to complete them. The surgery involved making a small incision (approximately 5 cm long) on the left anterior end proximal to the humerus and the covering tissue was then resected to expose the bone. A pilot hole, approximately 2 rnm in diameter, was drilled in the longitudinal axis of the bone. This subsequently enlarged to a diameter of 13 nm at a depth of approximately 4 to 5 cm to allow sufficient space for the pellets to be implanted. Four compressed pellets previously manufactured were implanted in the first three dogs, each stacked in such a way as to create a large cylinder. After the pellets were in place, the implants were covered by suturing the soft tissue over the hole and finally suturing the skin. Anterior-posterior and lateral radiographs were taken to visualize the implants following the surgery. It was interesting to note that on the third dog the X-rays clearly showed that the second most proximal pellet had rotated 90 ° so that the side (curved edge) of the cylinder was in contact with the plant surface of the pellet below.

For the three final dogs, access to the bone implant was achieved using the same procedure that was used for compressed pellets. The implants in this case, however, were made in place using the molding technique developed as described above. The surgery continued as in the case of the compressed pellets again became surgical radiographs. There was a definite distinction noted in the X-rays in the density of the two types of implants used. In the molded implants, some small gaps could be detected in the X-rays, but it was difficult to identify if they were on the surface or were empty. All the animals completed the 6 weeks of experimentation without surgical complications or adverse reactions. The levels of tobra icine in both serum and tissue were monitored in all experiments. The tobrarnicin assay was done using fluorescence, polarization and immunoassay technology. Serum levels were determined by submitting 3 to 5 ml of blood tests taken from the back of the leg through venipuncture for analysis. Samples were taken preoperatively (as comparison standards) as described above. The X-ray comparison pattern was used and after day 11 to monitor the placement of the hopodermic needle with respect to the implants for sample aspiration with respect to the tobramycin levels in serum and tissue. This was necessary since it was noted that the sample collection technique was critical to maintain consistency in the results of the experiment. Figure 12 shows the average levels of tobramycin for all 6 animals in the tissue assays. Starting from time 0, there is a maximum increase of tissue tobicalnicin at more than 60 μg / rnl @ hour 1 which decreases slowly to approximately 45 ug / rnl @ hours 3 and 24. A uniform decrease was observed from hour 24 to day 5 until a uniform state appears over the duration of the experiment (1 to 3 μg / ml). The serum level profile (Figure 13) is similar to the level in the tissue but at a much lower level. Starting at hour 0, a maximum serum level of 0.7 μg / rnl is reached and maintained until hour 3 and then decreases uniformly to 5. From 5 to 42, less than 0.1 μg / ml of tobramycin is detected in the serum and in many cases, there was no detectable amount present within the serum. A comparison of decomposition between the compressed and molded implants at the tissue levels shows similar profiles. Molded implants exhibit a higher initial increase at approximately 90 μg / ml and a uniform decrease at day 5 (Figure 14) at a relatively uniform level for days 7 to 42 (Figure 15). The compressed implants show similar profiles with a lower initial increase to approximately 50 and again the same decrease and uniform state. Figures 16 and 17 show the corresponding levels in the tobramycin serum for the two types of implants. X-rays were used to monitor the resorption tendencies of the implant during the course of the experiment. Measurements of the two dimensional X-rays were made and converted to surface area in crn2. Due to the amplification of the image, the values were normalized to reflect the actual sizes based on the known initial dimensions. Figure 18 shows a graph of the surface area with respect to time and it can be clearly seen that the resorption profiles of the two types of implants follow the same trend throughout the course of the study. The experiment was conducted at relatively low levels of tobramycin (approximately 160 to 170 rnl / procedure) compared to current surgical procedures in which as much as 1 to 2 grams of drug can be mixed with the bone cement for implantation. It is possible to use a higher level of drug loading (order of 5% by weight) to achieve an even greater effect. A comparison of these results in vivo with the in vitro results of Example 2 is shown in Table 11. The volume of the in vivo implants was approximated from the radiographic dimensions (converted to percent remnant) and the weights of the pellets. In vitro are from real measurements (converted to percent remnant), therefore, the solution can be plotted against time (Figure 19). The correlation coefficient for the two data sets is 0.923 indicating a relatively good correlation. These results indicate that sustained vibration of a drug from a localized area of a calcium sulfate matrix is achievable, while maintaining a low level of medication in the blood for a prolonged period.

TABLE 11 Percentage of the material that remains for pellets in vivo with respect to pellets in vitro

Claims (27)

NOVELTY OF THE INVENTION CLAIMS

1. - A pellet having a controllable dissolution rate, further characterized in that said pellet comprises: a powder consisting essentially of alpha-calcium sulfate hernihydrate and, optionally, powder consisting essentially of beta-calcium sulfate hernihydrate, in a solution which comprises water to form a mixture, and in that said powder consisting essentially of alpha-calcium sulfate hemihydrate has a purity greater than calcium sulfate hernihydrate at 98% by weight, a surface area of BET on the scale of approximately 0.4 m2 / ga approximately 0.9 rn2 / g, a density on the scale of about 2.73 to about 2.80 g / crn3, an average particle size of about 16 μm to about 22 μm, and because 90-95% by weight of the powder that consists essentially of alpha-calcium sulfate hemihydrate has a particle size distribution of about 1 μm to about 45 μm, because said powder which Essentially, beta-calcium sulfate hernihydrate has a purity greater than calcium sulfate hemihydrate at 98%, a surface area of BET on the scale of approximately 4.5 m2 / g, approximately 7.5 m2 / g, a density on the scale of about 2.5 g / cm3 to about 2.6 g / cm3, and an average particle size in the range of about 10 μm to about 15 μm, because the rate of dissolution of the pellet is controlled by varying the weight ratio of the powder essentially consisting of of beta-calcium sulfate has been hydrolyzed to the powder consisting essentially of alpha-calcium sulfate hernihydrate from 0 to about 3.

2. The pellet according to claim 1, further characterized in that the surface area of the powder essentially comprising of alpha-calcium sulfate hernihydrate is on the scale of approximately 0.4 rn2 / g approximately

0. 7 rn2 / g.

3. The pellet according to claim 1, further characterized in that the average particle size of powder consisting essentially of alpha-calcium sulfate hernihydrate is in the range of about 18 μm to about 22 μm.

4. The pellet according to claim 1, further characterized in that the surface area of the powder consisting essentially of beta-calcium sulphate hemihydrate is in the range of about 5 m2 / g to about 6 rn2 / g.

5. The pellet according to claim 1, further characterized in that the powder consisting essentially of beta-calcium sulfate hernihydrate is in the range of about 13 μ to about 14 μm.

6. The pellet according to claim 1, further characterized in that the ratio of the powder consisting essentially of beta-calcium sulfate hernihydrate to the powder consisting essentially of alpha-calcium sulfate hernihydrate is in the range of 0 to 0.33.

7. The pellet according to claim 1, further characterized in that said pellet also comprises medicament.

8. The pellet according to claim 7, further characterized in that the medicament is an antibiotic, a surgical agent, a growth factor or an analgesic.

9. The pellet according to claim 8, further characterized in that said antibiotic is tetracycline hydrochloride, vancornicin, tobramycin, gentanicin or cephalosporin.

10. The pellet according to claim 8, further characterized in that said chemotherapeutic agent is cis-β-latin, ifosfarnide, methotrexate or doxorubicin hydrochloride.

11. The pellet according to claim 8, further characterized in that said growth factor is a beta factor of growth transformation, morphogenic bone protein, basic growth factor of fibroblast derived platelet growth factor or other factors of polypeptide growth.

12. The pellet in accordance with claim 8, further characterized in that said analgesic is lidocaine hydrochloride, bipivacaine hydrochloride and ketorolac-rornetamine

13. The pellet according to claim 1, further characterized in that said solution also contains sodium chloride.

14. The pellet according to claim 1, further characterized in that the weight ratio of the water to the alpha-calcium sulphate hernihydrate and to the beta-calcium sulfate hemihydrate is in the range of approximately 0.22 to approximately 1.

15. - The pellet in accordance with the claim 14, characterized in that the weight ratio of water to alpha-calcium sulphate hemihydrate and beta-clathium sulphate hemihydrate is on the scale of approximately 0.27 to 0.30.

16. A method for repairing a pellet having a controllable rate of dissolution comprising pressurizing the mixture of claim 1, a powder consisting essentially of alpha-calcium sulfate hemihydrate and, optionally, powder consisting essentially of of beta-calcium sulfate hemihydrate, in a solution comprising water.

17. A method for repairing a pellet having a controllable rate of dissolution comprising molding the mixture according to claim 1, a powder consisting essentially of alpha-calcium sulfate hemihydrate and, optionally, powder consisting essentially of sulphate of beta-calcium hemihydrate, in a solution comprising water.

18. A composition having a controllable rate of dissolution, comprising water and an alpha-calcium sulfate hernihydrate having an average particle size of about 16 μm to about 22 μm.

19. The composition according to claim 18, further characterized in that 90-95% of said alpha-calcium sulphate hemihydrate has a particle size of about 1 μrn to about 45 μ.

20. The composition according to claim 18, further characterized in that the alpha-calcium sulfate hemihydrate has a purity greater than the calcium sulfate hemihydrate at 98% by weight.

21. The composition according to claim 18, further characterized in that the alpha-calcium sulfate hemihydrate has a density of about 2.73 to about 2.80 g / cm3.

22. The composition according to claim 18, further characterized in that the composition also comprises a medicament.

23. The composition according to claim 18, further characterized in that the weight ratio of the water to the alpha-calcium sulfate hemihydrate is from about 0.22 to about 1.

The composition according to claim 18, which it comprises, in addition to said alpha-calcium sulfate hemihydrate and water, a beta-calcium sulphate hernihydrate and further characterized in that the rate of dissolution is controlled by varying the weight ratio of said beta-calcium sulphate hemihydrate to said alpha sulfate. calcium hemihydrate from 0 to approximately 3.

The composition according to claim 18, further characterized in that 90-95% of said alpha-calcium sulfate hemihydrate has a particle size of about 1 μm to about 45 μm. .

26. A composition that releases a medicament at a controlled rate, further characterized in that said composition comprises water and an alpha-calcium sulfate hemihydrate and said medicament, because said composition is capable of releasing said medicament continuously for at least one week when It is implanted in the subcutaneous tissue of a Sprague Dowley rat.

27. The composition according to claim 26, further characterized in that said composition is capable of releasing said medicament continuously for at least 2 weeks.