An apparatus for simulating human traumatic brain injury in an animal, said apparatus comprising a support having an aperture having end walls and side walls disposed therein; a sliding element slidingly engaged with said side walls of said aperture, said sliding element having a retainer disposed thereon for receiving an animal holder therein; and a crank arm operatively connected to both said sliding element and an actuator mechanism. There is also disclosed a method of simulating human traumatic brain injury in an animal which includes the steps of providing an animal and repeatedly laterally displacing the animal in a reciprocal manner in order to cause acceleration and deceleration of the animal laterally to cause the animal""s brain to be correspondingly accelerated and decelerated thereby causing traumatic brain injury. A method of simulating human spinal cord injury in an animal, said method comprising the steps of providing a vertebrate animal having an invertebral space and a spinal cord; causing an opening in the animal at the invertebral space to the interior surface of the spinal cord; inserting a deflated balloon embolectomy catheter into the opening, and rapidly inflating the balloon catheter to cause the balloon catheter to expand and contact the spinal cord whereby the contact causes injury to the spinal cord.

The subject invention relates to an apparatus and method for simulating human central nervous system injuries and, more particularly, the subject invention relates to an apparatus and method for animal simulation of human traumatic brain injury and spinal cord injury.
The predominant mechanism in most cases of traumatic brain injury (TBI) is diffuse axonal injury (Whyte and Rosenthal, 1993). While axonal injury is common in all TBI regardless of severity (Povlishock et al., 1992; Mittl, 1994), a shearing of the axons occurs in human diffuse axonal injury (DAI) leading to progressive changes that ultimately may result in the loss of connections between nerve cells. The slow progression of events in DAI continues for up to several weeks after injury creating a window of opportunity for therapeutic intervention. Up to now, there are no consistently reproducible small animal models for DAI which closely mimic the changes associated with DAI in humans (Maxwell et al., 1997; Povlishock, 1993). Without such a model to study the mechanism of injury, it is difficult to develop prevention and/or interventional methodologies to limit the extent of injury. In part, this may explain the lack of efficacy of the clinical trials to assess various medications to limit injury in TBI.
There are approximately 500,000 new cases of TBI in the U.S. each year (Frankowski, 1985), and the incidence requiring hospitalization is estimated to be approximately 200-225/100,000 population (Frankowski, 1986; Carus, 1993). Currently, it is estimated that brain injuries account for 12% of all hospital admissions in the United States (Sandel, 1993). When compared to spinal cord injury, which accounts for less than 1% of hospital admissions, it is clear that TBI is a medical care problem which has a significant impact financially within the United States. Approximately 30,000-44,000 people will survive a severe TBI with GCS score less than 9 (Glasgow Coma Score Scale, Jennett, 1981) in the U.S. each year and more than 70,000 will be significantly disabled from moderate to severe TBI (GCSxe2x89xa610) (Whyte and Rosenthal, 1988). Yet with new medical management techniques, less than 10% will remain in a persistent vegetative state (Whyte, 1993; Rosner, 1992; Rosner, 1990). A GCS score of eight or less generally reflects a state of unconsciousness in which the patient demonstrates no eye opening, does not follow simple commands to move muscles, and has vocalizations which are limited to sounds. Such signs are indicative of severe brain injury (Whyte, 1993; Jennett, 1975, Jennett, 1981).
Approximately 52,000 to 56,000 people die each year from TBI (Kraus et al., 1996), resulting in direct costs approximated at more than $50 billion annually (Max et al., 1991). The costs of severe TBI to the individual and family are extremely high (McMordie, 1988). Acute medical and rehabilitation bills are often around $100,000 with some considerably higher (McMordie, 1988). The Model Systems Database for Traumatic Brain Injury demonstrates there is a correlation between the average Disability Rating Score and the combined acute care and rehabilitation charges (Bullock et al., 1995). Those with a severe TBI (GCS score of 6-8) have average combined charges of $110,842, and those with a very severe TBI (GCS score 3-5) have average combined charges of $154,256 (Lehmkuhl, 1993). About one-half of all TBIs are transportation related (Whyte, 1993; Lehmkuhl, 1993) and these patients have some of the highest combined charges for acute care and rehabilitations (Lehmkuhl, 1993). This may be related to the mechanism of TBI in high speed motor vehicle crashes, specifically the presence of diffuse axonal injury (DAI) being most prevalent in the midbrain and brain stem areas (Whyte, 1993). Clearly, brain injuries of this severity that occur with high speed acceleration-deceleration injuries, have the highest costs to society. TBI clearly causes more mortality, morbidity and probably more economic loss than HIV infection in the United States.
Motor vehicle crashes of all types are responsible for approximately 40%-50% of the TBI admissions recorded in the Model TBI Systems Database (Lehmkuhl, 1993). The predominant mechanism of injury is considered to be diffuse axonal injury (DAI). Approximately 30%-40% of the fatal head injuries involve diffuse axonal injury by pathological examination (Bennett et al., 1995; McLellan, 1990). However, based on beta-amyloid precursor protein immunostaining, axonal injury may be present in all cases of fatal head injury (Gentleman et al., 1995). In cases of persistent vegetative states, Kampfl et al. (1998) recently found that all cases had evidence of DAI in magnetic resonance imaging (MRI). Diffuse axonal injury occurs even in the absence of a blow to the head and is more prevalent than previously realized. Even in mild head injury, diffuse axonal injury is present in almost ⅓ of the cases (Mittl et al., 1994). The defining characteristic of DAI is the morphologic change to the axons which occurs over the course of several days to weeks and the fact that multiple regions of the brain are injured. While a component of DAI is present in blunt or penetrating trauma injury, it is at the periphery of the injury zone and is much less significant than the predominant mechanism of injury. DAI is the major mechanism of injury in high speed acceleration-deceleration injuries associated with motor vehicle crashes. While all four mechanisms of TBI (DAI, blunt trauma, penetrating trauma, axonia) may be involved in such an injury, it is the predominant mechanism of injury under this condition.
Diffuse axonal injury is only one of the cellular mechanisms of traumatic brain injury. The others include such things as direct contusion to the cells, intracerebral hemorrhage (blood across the blood brain barrier), perfusion-reperfusion injury, and anoxia. In a high velocity TBI such as those sustained in a car accident and the subsequent sequelae one can have several mechanisms of cellular injury. Each of these mechanisms appears to cause a unique area and type of TBI. This also indicates that each type of cellular injury activates different cellular pathways and cellular channels. For instance, the sequelae of brain injury from a subtype of intracerebral hemorrhage described as subarachnoid hemorrhage (both spontaneous and traumatic) appears to respond to L-type Ca channel blockers but these same substances have not been protective in another type of TBI (European Study Group on Nimodipine in Severe Head Injury, xe2x80x9cA Multicenter Trial of the Efficacy of Nimodipine on Outcome after Severe Head Injuryxe2x80x9d, J. Neurosurg., 1994, 80:797-804; Allen GS, Ahn, HS, Preziosi, TJ, et al., xe2x80x9cCerebral Arterial Spasmxe2x80x94a Controlled Trial of Nimodipine in Patients with Subarachnoid Hemorrhagexe2x80x9d, N. Eng. J. Med., 1983, 308:619-624). It is clear that other types of channels, including Ca channels, may be involved in other types of cellular injury.
In DAI, when enough force is applied to the cytoplasm of the neuronal cell, the elastic memory of the substance is exceeded. Then the amount of cytoplasmic deformation is directly related to the time the force is applied. This in turn relates to the amount of cytoskeletal disruption that occurs. Applicant""s work has proven, with this device, that the severity of neuronal injury that occurs when a rat is injured at a defined Hertz is related to the length of time the force is applied. Furthermore, that many of the same areas of the brain have cellular disruption (corpus callosum, mesencephalon and brain stem) as is noted in humans who have suffered high velocity TBI as is noted in motor vehicle crashes. It is understood that many who have suffered a TBI in a cause similar to a motor vehicle crash may have more than one mechanism of neural cell injury. The injury inducing methods enabled by this machine will allow applicant""s to analyze the causes and the subsequent effects of DAI on neuronal cells and allow testing of unique compounds to protect against further neural cell death and injury without any of the other confounding, and many times masking, causes of neural cell injury being involved. In the model described the cellular disruption was not accompanied by intracerebral hemorrhage, or contusion and does not involve primarily perfusion-reperfusion or anoxic injury to the neuronal cells. By limiting the type of injury to a single type, applicant""s can now study the mechanism of injury, its biochemical interactions and unique compounds to protect against neural cell injury. The foundation of the inventions in this application is its isolation of this single injury type, and the subsequently derived methods of testing for mitigation, methods of investigative research, and methods of treatment based on this uniquely isolated injury type. This is also important because DAI is, in many cases, especially in auto and other inertia caused injuries, the predominate injury type.
Many of the areas that are injured in DAI are contiguous to the areas of cerebrospinal fluid (CSF) circulation in the brain. They are thus readily accessible to treatment via diffusion with substances delivered into the CSF for circulation and such diffusion into the injured areas.
For human head injuries resulting from car collisions, the average velocity for the onset of severe injuries is 6.7 m/s (or 24.1 km/hour) as mentioned by Lorenzo et al. (1996). Most studies have been directed to the analysis of impact to the head. The Head Injury Criterion (HIC) is one method that is commonly used to assess the severity of an impact (Chou and Nyquist, 1974). Although it is considered to be the best available head injury indicator, a new finite element model using a dummy head has taken into account the effects of rotational and translational acceleration (Ueno and Melvin, 1995). Using this model, the dominant effect of translational acceleration was on principal stresses and rotational acceleration was on shear stresses.
Based on studies of head injury in primates (including man), some of the mechanical forces which bring about DAI (McLellan, 1990) have been elucidated. The crucial factors are (1) the type of acceleration/deceleration (angular rather than translational), (2) the duration of acceleration/deceleration (long rather than short), and (3) the direction of head movement (coronal rather than sagittal). Clearly angular acceleration or the associated sudden deceleration associated with an xe2x80x9cimpactxe2x80x9d will create forces above the threshold level (McLean and Anderson, 1997). Indeed most, but not all shaken baby syndromes are characterized by a sudden deceleration (Duhaime et al., 1998).
Current research appears to point of plastic deformation within and of the axons that leads to the predominant cause of injury. The elastic tissues of the brain have plastic properties. Once the level of force is applied to a plastic substance, it is the time period over which it is applied that causes the amount of deformation. If the elastic memory of the substance is exceeded then there will be shearing and tearing. The high speed motor vehicle accident with deceleration lasting more than one to three seconds or several seconds of repetitive shaking can produce enough force for this to happen.
Materials research indicates that there is an amount of force which must be delivered below which plastic deformation of substances does not occur. In fact, the Gadd severity index initially attempted to measure the severity of injury utilizing an acceleration/time curve (Gadd, 1998). This critical amount of force appears to be essential in the development of injury (McLean and Anderson, 1997). This is very different from the contusive model of TBI where the forces are applied over milliseconds.
In nonhuman primates, this type of DAI has been induced utilizing a non-impact rotational device (Marguiles et al., 1990; Kobayashi et al., 1989). However, nonhuman primates are expensive models with significant limitations that do not lend themselves to extensive preclinical pharmaceutical and interventional trials. In rats, some DAI is found around the area of contusive injury (Meaney, 1994) but this is likely due to a small amount of localized shear forces. The sites of injury in a contusive model in rats do not conform to the areas of the brain associated with human injuries: the brain stem, corpus callosum and midbrain (Blumbergs, 1994).
More evidence is available on the mechanism of injury from the so-called xe2x80x9cshaken baby syndromexe2x80x9d (Nelson et al., 1993). This mechanism of injury induces a DAI due to shaking the infant in a repeated coronal plant with or without rotational forces and there are often associated injuries to the optic nerve with this type of injury (Nelson et al., 1993). In animals, repeated coronal shaking of the head has been reported to produce some DAI utilizing miniature pigs (Ross et al., 1994; Kimura et al., 1996; Smith et al., 1997). In addition, similar histopathologic findings to the optic nerve injuries associated with the xe2x80x9cshaken baby syndromexe2x80x9d have been noted after direct stretching of the optic nerves of guinea pigs (Maxwell et al., 1997).
This indicates that once the amount of force has reached a threshold, it is the length of time the force is applied with the associated plastic deformation that is the predominant factor which causes the intracellular damage to the organelles within the axon. Hence, there is a continuum over which DAI occurs in TBI. After the threshold of necessary force to create plastic deformation is reached, it may be the length of time over which it is applied that determines the amount of DAI. This would explain the findings of Foda et al. (1994) where some DAI was noted in areas adjacent to a contusion injury in rats. Unfortunately, most TBI occurs over several seconds (high speed transportation crashes) where DAI is likely to be the predominant method of injury. This is supported by the fact that many severe TBI patients have minimal changes noted on CT scan following motor vehicle crashes.
Motor vehicle crashes are the predominant cause of DAI. A component of DAI is felt to be present in all motor vehicle crashes where the patient has lost consciousness (Whyte, 1988). For many years, DAI has been known to be associated with a coma of immediate onset after brain injury, but the diagnosis could only be established by autopsy. Indeed, the clinical syndrome of coma without any preceding lucid interval, decerebration, and autonomic dysfunction were often ascribed to primary brainstem injury. However, it is now clear that primary brainstem lesions do not occur in isolation but rather in association with DAI and usually involve the cerebral hemispheres and cerebellum in addition to the brainstem (McLellan, 1990). Evidence of the mechanism of injury can be elicited by pathological studies of patients killed from high speed transportation injuries (Pounder, 1997) as well as pathological studies of xe2x80x9cshaken baby syndrome,xe2x80x9d a distinct subset of DAI (Nelson et al. 1993). A recent case report (Pounder, 1997) indicates that this shaking mechanism of DAI injury also applies to adults. The injury is characterized by specific neuropathological findings. On CT and MRI, this usually involves hemorrhagic punctate lesion of the corpus callosum, pontine-mesencephalic junction adjacent to the superior cerebellar peduncles and diffuse axonal damage in the white matter of the brain, brainstem and cerebellum which begin to atrophy within two weeks after injury (Whyte, 1988; Blumbergs, 1994).
Diffuse axonal injury in humans is characterized by widespread damage to axons in the cerebral hemispheres, the cerebellum and the brain stem and is a consistent feature of TBI (Adams, 1977; Adams, 1989; McLellan, 1990). The histological features of DAI depend on the length of time after injury, but within a day or so after injury there is evidence of damage to axons in the form of axonal bulbs. The initial findings are usually characterized microscopically utilizing neurofibrillar stains and stains for microglia which are abundant in the degenerating white matter. These findings are produced by the shear or flow of cytoplasm from the proximal end of a severed axon. Subsequently, the microscopic features correspond to Wallerian-type axonal degeneration as the axon disintegrates, which is probably due to metabolic disruption from injury and damage to the internal organelles from the lack of membrane integrity. In the first two years there is active myelin degeneration and in patients surviving longer, demyelination is the final stage of the process (McLellan, 1990). The result of the traumatic injury to the axons leads to the disconnection with various target sites, which is assumed to translate into the morbidity seen (Gennarelli, 1982; Povlishock, 1992). The severity of injury based on the histopathological changes has been graded in humans but not in experimental animals (Adams, 1977; Adam, 1989). The Adams classification (Adams, 1977; Adams, 1989) is used in human autopsy material, to classify the degree of DAI as mild, moderate or severe. In this classification, mild (grade 1) is characterized by microscopic changes in the white matter of the cerebral cortex, corpus callosum, and brain stem and occasionally in the cerebellum. Moderate (grade 2) is defined based on focal lesions in the corpus callosum. In severe (grade 3), there are additional focal lesions in the dorsolateral quadrants of the rostral brain stem (commonly in the superior cerebellar peduncle). This scheme has not been used for non-primate models because different regions of the brain are injured in the present models. However, it may be possible to apply this scheme to an appropriate model of DAI in small animals that is currently under development.
It has been difficult to correlate the severity of injury in humans with animal models. Animals cannot be accurately assessed by the Glasgow Coma Scale (Jennet, 1981), the Disability Rating Scale (Rappaport, 1982) or the length of post traumatic amnesia (Bishara, 1992). However, there are methods to measure the balance of animals and test their spatial memory and learning acquisition. Although non-human primates most closely resemble humans, monkeys are expensive to study. Most preclinical pharmacological studies involve rats because they are easily studied and relatively inexpensive so that large scale testing can be done. Yet, there has been no reliable reproducible rat model for DAI in the literature. There are problems, clearly the anatomy and geometry of the rat brain are less similar to the human brain than a monkey. However, by using engineering to replicate the mechanical aspects of diffuse axonal injury, the changes that occur in the rat brain are projected to be quite similar to the human condition.
The two most common animal models of human head injury are the fluid percussion and impact acceleration or weight-drop method. Fluid percussion models produce brain injury by rapidly injecting saline or blood into the closed cranium either at the midline (McIntosh et al. 1984) or laterally (McIntosh et al., 1989a). Unfortunately, these are not ideal models of human diffuse axonal injury. The models more closely replicate some of the features of subarachnoid hemorrhage. The impact acceleration (Lighthall, 1988) and the weight-drop methods (Shohami et al., 1994) both involve creating an indentation into the brain. Although some diffuse axonal injury occurs with these models, DAI is present in different areas and involve a disproportionately small volume than in humans. In order to develop a better animal model that includes diffuse axonal injury in the forebrain as is characteristic of human diffuse axonal injury, Meaney and colleagues in 1994 modified the impact-acceleration model. This new cortical impact model involves creating an indentation (1.5 mm indentation, 4.7 m/sec velocity, 22 msec dwell time) on the motor cortex combined with a contralateral craniotomy. Unfortunately, this model still lacks many features of human diffuse axonal injury. Yet another model of DAI in rats, involves dropping a weight onto a metallic disc fixed to the skull (Foda and Marmarou, 1994). Although some features of human diffuse axonal injury are seen, there are considerable amounts of brain edema and neuronal injury directly under the area of impact. This model was designed to create enough energy to reach the threshold for which some DAI will develop (McLean and Anderson, 1997). However, in models where DAI is found secondary to a contusive injury, studies directed at evaluating a treatment for DAI will be severely hindered.
In animals, repeated coronal shaking of the head has been reported to produce some DAI utilizing miniature pigs (Ross et al., 1994; Kimura et al., 1996; Smith et al., 1997). In addition, similar histopathologic findings to the optic nerve injuries associated with the xe2x80x9cshaken baby syndromexe2x80x9d have been noted after direct stretching of the optic nerves of guinea pigs (Maxwell et al., 1997). In nonhuman primates, this type of DAI has been induced utilizing a non-impact rotational device (Marguiles et al. 1990; Kobayashi et al., 1989). However, nonhuman primates are expensive models with significant limitations that do not lend themselves to extensive preclinical pharmaceutical and device interventional trials.
Maxwell, Povlishock and Graham (1997) states that with the current animal models of diffuse axonal injury, axonal injury does not occur in the parasagittal white matter or corpus callosum which are the most frequent sites of axonal injury in human diffuse axonal injury. They go on to suggest that the term xe2x80x9cdiffuse axonal injuryxe2x80x9d mot be used in animal models because the animal models differ from human diffuse axonal injury. The most similar model to human DAI was a primate model of DAI in which monkeys were exposed to acceleration and deceleration in the oblique, lateral and sagittal planes (Gennarelli, 1982). While the injury induced was similar to humans, primate models are prohibitively expensive when considering preclinical therapeutic interventions.
All of the clinical trials evaluating treatments for traumatic brain injury have failed. The reason for this failure may be the lack of an adequate injury model in small experimental animals such as rats and mice. An injury model that closely mimics human injury is essential in developing and evaluating treatments for patients with head injury. Applicants"" efforts have been directed at producing a small animal model for the most common type of traumatic head injury called diffuse axonal injury (DAI).
The subject invention provides a small animal model that closely resembles human DAI, and essentially only DAI, in order to develop a successful treatment for DAI patients.
Similar to TBI models, in trying to develop a treatment for spinal cord injury, a critical step is to have a model that closely mimics the typical human injury. In most human spinal cord injuries, the force is directed from the anterior direction either from a burst fracture or a retropulsed disc. The force upon the spinal cord is not removed until traction or decompressive surgery can be performed. Swelling of the spinal cord occurs after injury. A new method of creating a spinal cord injury in animals has been developed to replicate the characteristics of a typical human spinal cord injury.
Heretofore, the most common model of spinal cord injury is the weight-drop method. The disadvantages of this method are: 1) the spinal cord is decompressed before injury, 2) the force is directed posteriorly, and 3) a transient force is applied upon the cord. The decompression is done before injury because it is necessary to perform a laminectomy (bone removed from the posterior surface of the spinal cord) before the weight is dropped onto the surface of the spinal cord. Removal of the bone allows room for expansion of the spinal cord as it swells after injury. The force is directed from the dorsal direction because it is very difficult to surgically approach the spinal cord from the dorsal direction especially in the case of an injury to the thoracic cord. The force upon the spinal cord is transient because the force is only from the impact of the weight. The advantage to this method is that it produces a contusive injury and that it can be replicated.
Another method that is used to injure the spinal cord is to cut the cord with a hemisection or transection. The disadvantage to this technique is that the cord in humans is only rarely cut but most often receives a contusive injury. The advantage to this method is that can easily be used to measure new growth of nerve cell processes.
Accordingly, it would be advantages and desirable to have accurate animal models of both TBI and spinal cord injury which closely approximate human TBI and spinal cord injury which overcome the drawbacks and disadvantages of the models described above and which isolates injury to essentially or substantially only DAI.
There is provided an apparatus for simulating human traumatic brain injury in an animal which includes a support having an aperture having end walls and side walls disposed therein. A sliding element is slidingly engaged with the side walls of the aperture and includes a retainer disposed thereon for receiving a human holder therein. A crank arm is operatively connected to both the sliding element and an actuator mechanism.
There is also disclosed a method of simulating human traumatic brain injury in an animal which includes the steps of providing an animal and repeatedly laterally displacing the animal in a reciprocal manner in order to cause acceleration and deceleration of the animal laterally to cause the animal""s brain to be correspondingly accelerated and decelerated thereby causing traumatic brain injury.
There is also provided a method of simulating human spinal cord injury in an animal which includes the steps of providing a vertebrate animal having an invertebral space and a spinal cord. An opening is placed in the animal at the invertebral space to the interior surface of the spinal cord and a deflating embolectomy catheter is inserted into the opening. The embolectomy catheter is then rapidly inflated to cause the balloon catheter to expand and contact the spinal cord whereby the contact causes injury to the spinal cord.

Apparatus for simulating traumatic brain injury and method for inducing spinal cord injury


Aqueous oral and dental care compositions are comprising of: (a) from about 0.1 to about 20% by weight of surfactant granules which are the product of the process which comprises subjecting an aqueous paste comprised of from about 40 to about 60% by weight of a monoglyceride (ether) sulfate to simultaneous drying and granulation in a fluidized bed; (b) from about 1 to about 25% by weight of an abrasive, a polish, or a combination thereof; (c) from 0 to about 65% by weight of a humectant; (d) from 0 to about 2% by weight of chitosan; (e) from 0 to about 3% by weight of a flavoring and; (f) from 0 to about 5% by weight other auxiliaries including water wherein the weight of all components adds up to 100% by weight.

This invention relates to the use of special surfactant granules for the production of surface-active compositions, preferably detergents, soaps and oral and dental care preparations.
1. Prior Art
Monoglyceride (ether) sulfates are acquiring increasing significance for use in surface-active compositions by virtue of their excellent detersive properties. Hitherto, they have generally been used in the form of water-containing preparations. A major disadvantage of this is that these pastes generally contain between 50 and 75% by weight of water in order to be sufficiently pumpable. On the market, however, there is a heavy demand for solid water-free supply forms which can be incorporated in particular in powder-form detergents, tooth creams or syndet soaps without having to be dried beforehand.
Solid monoglyceride (ether) sulfates obtained, for example, by drying and simultaneous granulation in a thin layer in a so-called flash dryer are known from the prior art (DE 19641275 C1). Unfortunately, the surfactants produced in this way have unsatisfactory dissolving properties in detergents.
Accordingly, the problem addressed by the present invention was to provide a solid supply form of monoglyceride (ether) sulfates which could be prepared with a little water and which would be distinguished by improved dissolving behaviour in laundry detergents, dishwashing detergents and cleaning compositions.
2. Description of the Invention
The present invention relates to surfactant granules obtainable by subjecting 20 to 60% by weight and preferably 40 to 50% by weight aqueous pastes containing monoglyceride (ether) sulfates to simultaneous drying and granulation in a fluidized bed.
The present invention also relates to the use of these surfactant granules for the production of surface-active compositions, preferably oral and dental care preparations.
It has surprisingly been found that the drying and granulation of aqueous surfactant pastes in a fluidized bed (xe2x80x9cSKET granulationxe2x80x9d) leads to solid supply forms of the monoglyceride (ether)sulfate which are distinguished by excellent dissolving behavior in laundry detergents, dishwashing detergents and cleaning compositions. In addition, monoglyceride (ether) sulfate granules produced in this way have an abrasive effect in oral and dental care preparations and may therefore be used as a substitute for other abrasives. This has the particular advantage that the quantity of abrasives can be reduced without any effect on abrasive performance. Bar soaps containing monoglyceride (ether) sulfate granules as surfactant component are distinguished by good foaming behavior, better stability in air and a reduced tendency towards softening.
In combination with other surfactants, especially fatty alcohol sulfates, sulfosuccinates, olefin sulfonates, alkyl and/or alkenyl oligoglycosides, a synergistic improvement in the properties mentioned is observed. In addition, where these granules are used in the described compositions, there is no need for the removal of water which would be necessary if comparable aqueous pastes were used.
Monoglyceride sulfates and monoglyceride ether sulfates are known anionic surfactants which may be obtained by the relevant methods of preparative organic chemistry. They are normally produced from triglycerides which, optionally after ethoxylation, are transesterified to the monoglycerides and then sulfated and neutralized. The partial glycerides can also be reacted with suitable sulfating agents, preferably gaseous sulfur trioxide or chlorosulfonic acid [cf. EP 0 561 825 B1, EP 0 561 999 B1 (Henkel)]. If desired, the neutralized products may be subjected to ultrafiltration to reduce their electrolyte content to the required level [DE 42 04 700 A1 (Henkel)]. Overviews of the chemistry of monoglyceride sulfates have been published, for example, by A. K. Biswas et al. In J. Am. Oil. Chem. Soc. 37, 171 (1960) and F. Ahmed in J. Am. Oil. Chem. Soc. 67, 8 (1990). The monoglyceride (ether) sulfates suitable for use in accordance with the invention correspond to formula (I):
in which R1CO is a linear or branched acyl group containing 6 to 22 carbon atoms, x, y and z together stand for 0 or for numbers of 1 to 30, preferably 2 to 10, and X is an alkali metal or alkaline earth metal. Typical examples of monoglyceride (ether)sulfates suitable for the purposes of the invention are the reaction products of lauric acid monoglyceride, coconut fatty acid monoglyceride, palmitic acid monoglyceride, stearic acid monoglyceride, oleic acid monoglyceride and tallow fatty acid monoglyceride and ethylene oxide adducts thereof with sulfur trioxide or chlorosulfonic acid in the form of their sodium salts. Monoglyceride sulfates corresponding to formula (I) in which R1CO is a linear acyl group containing 8 to 18 carbon atoms and preferably 12 to 14 carbon atoms, x, y and z=0 and X is sodium are preferably used.
In one preferred embodiment of the invention, aqueous pastes containing fatty alcohol sulfates, sulfosuccinates, olefin sulfonates, alkyl and/or alkenyl oligoglycosides as further surfactants are dried and granulated. Alternatively, the monoglyceride (ether) sulfate granules may be present in admixture with granules of fatty alcohol sulfates, sulfosuccinates, olefin sulfonates, alkyl and/or alkenyl oligoglycosides such as, for example, monoglyceride (ether) sulfate, fatty alcohol sulfate, alkyl and/or alkenyl oligoglycoside granules.
Fatty alcohol sulfates are understood to be primary aliphatic alkyl sulfates corresponding to formula (II):
R2Oxe2x80x94SO3Xxe2x80x83xe2x80x83(II)
in which R2 is a linear or branched, saturated or unsaturated hydrocarbon radical containing 12 to 14 carbon atoms and X is an alkali metal and/or alkaline earth metal, ammonium, alkyl ammonium, alkanolammonium or glucammonium. Fatty alcohol sulfates are known anionic surfactants which are preferably obtained by sulfation of native fatty alcohols or synthetic oxoalcohols and subsequent neutralization. Typical examples of fatty alcohol sulfates are the sodium salts of sulfation products of lauryl alcohol, isotridecyl alcohol, myristyl alcohol and the technical mixtures thereof obtained, for example, in the high-pressure hydrogenation of technical methyl esters based on fats and oils or aldehydes from Roelen""s oxo synthesis and as monomer fraction in the dimerization of unsaturated fatty alcohols. Fatty alcohols containing 12 to 14 carbon atoms such as, for example, technical C12/14 coconut alcohol sulfates and, more particularly, lauryl alcohol are preferably used.
Sulfosuccinates, which are also referred to as sulfosuccinic acid esters, are known anionic surfactants which may be obtained by the relevant methods of preparative organic chemistry. They correspond to formula (III):
where R3 is an alkyl and/or alkenyl group containing 6 to 22 carbon atoms, R4 has the same meaning as R3 or X, n and m independently of one another stand for 0 or for numbers of 1 to 10 and X is an alkali metal or alkaline earth metal, ammonium, alkylammonium, alkanolammonium or glucammonium. They are normally produced from maleic acid, but preferably from maleic anhydride, which in a first step is esterified with optionally ethoxylated primary alcohols. The monoester-to-diester ratio can be adjusted at this stage by varying the quantity of alcohol and the temperature. The second step comprises the addition of bisulfite which is normally carried out in methanol as solvent. Fairly recent overviews of the production and use of sulfosuccinates have been published, for example, by T. Schoenberg in Cosm. Toil. 104, 105 (1989), by J. A. Milne in R. Soc. Chem. (Ind. Appl. Surf. II) 77, 77 (1990) and by W. Hreczurch et al in J. Am. Oil. Chem. Soc. 70 707 (1993). Typical examples are sulfosuccinic acid monoesters and/or diesters in the form of their sodium salts which are derived from fatty alcohols containing 8 to 18 and preferably 8 to 10 or 12 to 14 carbon atoms. The fatty alcohols may be etherified with on average 1 to 10 and preferably 1 to 5 moles of ethylene oxide and may have both a conventional andxe2x80x94preferablyxe2x80x94a narrow homolog distribution. Di-n-octyl sulfosuccinate and monolauryl-3EO-sulfosuccinate in the form of their sodium salts are mentioned as examples.
Alkyl and/or alkenyl oligoglycosides are known nonionic surfactants which correspond to formula (IV):
R5Oxe2x80x94[G]pxe2x80x83xe2x80x83(IV)
where R5 is an alkyl and/or alkenyl radical containing 4 to 22 carbon atoms, G is a sugar unit containing 5 or 6 carbon atoms and p is a number of 1 to 10. They may be obtained by the relevant methods of preparative organic chemistry. The synoptic articles by Biermann et al. in Starch/Stxc3xa4irke 45, 281 (1993), B. Salka in Cosm. Toil. 108, 89 (1993) and J. Kahre et al. in Sxc3x96FW-Journal No. 8, 598 (1995) are cited as representative of the extensive literature available on this subject.
The alkyl and/or alkenyl oligoglycosides may be derived from aldoses or ketoses containing 5 or 6 carbon atoms, preferably glucose. Accordingly, the preferred alkyl and/or alkenyl oligoglycosides are alkyl and/or alkenyl oligoglucosides. The index p in general formula (IV) indicates the degree of oligomerization (DP), i.e. the distribution of mono-and oligoglycosides, and is a number of 1 to 10. Whereas p in a given compound must always be an integer and, above all, may assume a value of 1 to 6, the value p for a certain alkyl oligoglycoside is an analytically determined calculated quantity which is generally a broken number. Alkyl and/or alkenyl oligoglycosides having an average degree of oligomerization p of 1.1 to 3.0 are preferably used. Alkyl and/or alkenyl oligoglycosides having a degree of oligomerization of less than 1.7 and, more particularly, between 1.2 and 1.4 are preferred from the applicational point of view. The alkyl or alkenyl radical R5 may be derived from primary alcohols containing 4 to 11 and preferably 8 to 10 carbon atoms. Typical examples are butanol, caproic alcohol, caprylic alcohol, capric alcohol and undecyl alcohol and the technical mixtures thereof obtained, for example, in the hydrogenation of technical fatty acid methyl esters or in the hydrogenation of aldehydes from Roelen""s oxosynthesis. Alkyl oligoglucosides having a chain length of C8 to C10 (DP=1 to 3), which are obtained as first runnings in the separation of technical C8-18 coconut oil fatty alcohol by distillation and which may contain less than 6% by weight of C12 alcohol as an impurity, and also alkyl oligoglucosides based on technical C9/11 oxoalcohols (DP=1 to 3) are preferred. In addition, the alkyl or alkenyl radical R5 may also be derived from primary alcohols containing 12 to 22 and preferably 12 to 14 carbon atoms. Typical examples are lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, arachyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol, brassidyl alcohol and technical mixtures thereof which may be obtained as described above. Alkyl oligoglucosides based on hydrogenated C12/14 coconut oil fatty alcohol having a DP of 1 to 3 are preferred.
The compositions according to the invention contain as a further constituent olefin sulfonates which are normally obtained by addition of SO3 onto olefins corresponding to formula (V):
R6xe2x80x94CHxe2x95x90CHxe2x80x94R7xe2x80x83xe2x80x83(V)
in which R6 and R7 independently of one another represent H or alkyl groups containing 1 to 20 carbon atoms, with the proviso that R6 and R7 together contain at least 6 and preferably 10 to 16 carbon atoms, and subsequent hydrolysis and neutralization. Particulars of their production and use can be found in a synoptic article published in J. Am. Oil. Chem. Soc. 55, 70 (1978).
Internal olefin sulfonates may be used although xcex1-olefin sulfonates which are obtained where R6 or R7 is hydrogen are preferably used. Typical examples of the olefin sulfonates used are the sulfonation products obtained by reacting SO3 with 1-, 2-butene, 1-, 2-, 3-hexene, 1-, 2-, 3-, 4-octene, 1-, 2-, 3-, 4-, 5-decene, 1-, 2-, 3-, 4-, 5-, 6-dodecene, 1-, 2-, 3-, 4-, 5-, 6-, 7-tetradecene, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-hexadecene, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-octadecene, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-eicosene and 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10- and 11-docosene. The sulfonation is followed by hydrolysis and neutralization, after which the olefin sulfonate is present in the mixture as an alkali metal, alkaline earth metal, ammonium, alkyl ammonium, alkanolammonium or glucammonium salt and preferably as a sodium salt. The hydrolyzed xcex1-olefin sulfonation product, i.e. the xcex1-olefin sulfonates, advantageously consists of ca. 60% by weight of alkane sulfonates and ca. 40% by weight of hydroxyalkane sulfonates, of which 80 to 85% by weight are monosulfonates and 15 to 20% by weight disulfonates.
Besides the drying and granulation of neutralized surfactant pastes, it is also possible to subject the acidic sulfonation products to spray neutralization as described, for example, in EP 0 319 819 A1. In this process, the acid and a highly concentrated aqueous sodium hydroxide solution are separately exposed to a gaseous medium, subsequently combined in stoichiometric quantities, neutralized in a multicomponent nozzle and sprayed into the dryers or granulators under a high propellent gas pressure.
Since the sulfation is never complete, above all in industrial installations, conventional alkyl sulfate pastes always contain unsulfonated components. In the case of monoglyceride sulfates, these unsulfonated components are understood to be the unreacted monoglycerides. The aqueous alkyl sulfate pastes normally contain the unsulfonated components in quantities of 0.2 to 10, preferably 0.4 to 5 and more preferably 0.6 to 0.8% by weight, based on the active substance content. Aqueous technical monoglyceride (ether) sulfate pastes contain between 0.6 and 10% by weight of unsulfonated components and 10 to 50, preferably 15 to 45 and more particularly 20 to 35% by weight of technical coconut monoglyceride sulfate sodium salt. The balance of the pastes to 100% by weight is water and salts (0.1 to 20 and preferably 0.5 to 5% by weight, based on the active substance content).
A preferred possibility is to subject the water-containing surfactant paste to so-called SKET granulation. SKET granulation is understood to be a simultaneous granulation and drying process preferably carried out in batches or continuously in a fluidized bed. To this end, aqueous pastes of anionic surfactants and the liquid intermediate products are introduced simultaneously or successively into the fluidized bed through one or more nozzles. Preferred fluidized-bed arrangements have base plates measuring 0.4 to 5 m. The SKET granulation is preferably carried out at fluidizing air flow rates of 1 to 8 m/s. The granules are preferably discharged from the fluidized bed via a sizing stage. Sizing may be carried out, for example, by means of a sieve or by an air stream flowing in countercurrent (sizing air) which is controlled in such a way that only particles beyond a certain size are removed from the fluidized bed while smaller particles are retained in the fluidized bed. The inflowing air is normally made up of the heated or unheated sizing air and the heated bottom air. The temperature of the bottom air is between 80 and 400xc2x0 C. and preferably between 90 and 350xc2x0 C. A starting material, preferably SKET granules from an earlier test batch, is advantageously introduced at the beginning of the SKET granulation process. The water from the fatty anionic surfactant paste evaporates in the fluidized bed, resulting in the formation of partly dried to fully dried nuclei which are coated with further quantities of anionic surfactant and the liquid intermediate product, granulated and again simultaneously dried. The dried granules contain 1 to 2% by weight of residual water. Reference is made in this connection to the teaching of German patent applications DE 4303211 A1 and DE 4303176 A1 of which the disclosures are hereby specifically included in the present specification.
One advantage of the granules is that they are non-tacky and have high bulk densities of 300 to 1,200 g/l and preferably 500 to 800 g/l.
The surfactant granules produced in accordance with the invention are used for the production surface-active compositions. The surface-active compositions in question may be laundry detergents, dishwashing detergents, cleaners, fabric softeners and cosmetic preparations for the cleaning and care of skin and hair. They are preferably used for the production of soaps and oral and dental care preparations.
According to the invention, the surfactant granules produced in accordance with the invention may be used on their own or in combination with the surfactant granules mentioned in quantities of 0.1 to 60, preferably 0.5 to 45 and more particularly 0.6 to 20% by weightxe2x80x94based on the preparations and expressed as solidsxe2x80x94in surface-active compositions, preferably soaps and oral and dental care preparations. Preferably 0.1 to 20, more preferably 0.5 to 15 and most preferably 0.6 to 45% by weight of the surfactant granulesxe2x80x94as described abovexe2x80x94are used in soaps and 0.1 to 20 and more particularly 0.6 to 5% by weight in oral and dental care preparations. The surfactant granules according to the invention and the surfactant granules mentioned are used in a ratio to one another of 20:80 to 80:20, preferably 30:70 to 70:30 and more particularly 40:60 to 60:40 parts by weight.
Besides the granules according to the invention, the laundry/dishwashing detergents and cleaners may contain other typical ingredients such as, for example, anionic surfactants, nonionic surfactants, builders, bleaching agents, bleach activators, detergency boosters, enzymes, enzyme stabilizers, redeposition inhibitors, optical brighteners, soil repellents, foam inhibitors, inorganic salts and dyes and perfumes.
The surfactant mixtures according to the invention may be used for the production of cosmetic preparations, for example hair shampoos, hair lotions, foam baths, shower baths, creams, gels, lotions, emulsions, wax/fat compounds, stick preparations or powders. These preparations may also contain mild surfactants, oil components, emulsifiers, superfatting agents, pearlizing waxes, consistency factors, thickeners, polymers, silicone compounds, fats, waxes, stabilizers, biogenic agents, deodorizers, anti-dandruff agents, film formers, swelling agents, UV protection factors, antioxidants, hydrotropes, preservatives, insect repellents, self-tanning agents, solubilizers, perfume oils, dyes, germ inhibitors and the like as further auxiliaries and additives.
The bar soaps, preferably syndet soaps, may contain water-soluble or water-swelling structurants, for example starch, preferably wheat or corn starch, as builders. Other suitable builders are fine-particle, water-insoluble alkali metal aluminium silicates, the use of synthetic crystalline sodium alumosilicates containing bound water, more especially zeolite A, being particularly preferred. Zeolite NaX and mixtures thereof with zeolite NaA may also be used. Suitable zeolites have a calcium binding capacity of 100 to 200 mg CaO/g. NTA and/or EDTA may also be used as liquid builders. Suitable plasticizers are fatty alcohols, fatty acid partial glycerides or wax esters containing 12 to 22 carbon atoms in the fatty components.
The surfactant granules according to the invention may be used for the production of oral and dental care preparations. These preparations may contain abrasives and polishes, flavoring components, chitosans and other typical ingredients for toothpastes as further auxiliaries and additives.
The compositions according to the invention may contain chalk, dicalcium phosphate, sodium bicarbonate, sodium sulfate, insoluble sodium metaphosphate, aluminium silicate, layer silicates, hydrotalcites, calcium pyrophosphate, fine-particle synthetic resins, silicas, aluminium oxide, aluminium oxide trihydrate, talcum, zeolites, magnesium aluminium silicate (Veegum(copyright)), calcium sulfate, magnesium carbonate and/or magnesium oxide as abrasives and polishes. The percentage content of the abrasives and polishes may be from 1 to 25% by weight and is preferably from 10 to 20% by weight, based on the final compositions.
Besides the surfactants mentioned, other suitable auxiliaries and additives are flavoring components, for example peppermint oil, spearmint oil, anise oil, Japanese anise oil, caraway oil, eucalyptus oil, fennel oil, cinnamon oil, clove oil, geranium oil, sage oil, pimento oil, thyme oil, marjoram oil, basil oil, citrus oil, gaultheria oil or one or more components of these oils isolated from them or synthetically produced such as, for example, menthol, carvone, anethol, cineol, eugenol, cinnamaldehyde, caryophyllene, geraniol, citronellol, linalool, salvia, thymol, terpinene, terpineol, methyl chavicol and methyl salicylate. Other suitable flavoring agents are, for example, methyl acetate, vanillin, ionone, linalyl acetate, rhodinol and piperitone. Suitable sweetening agents are either natural sugars, such as sucrose, maltose, lactose and fructose, or synthetic sweeteners such as, for example, saccharin sodium salt, sodium cyclamate or aspartame. The flavoring components may make up from 0 to 3% by weight and preferably from 1 to 2% by weight of the final compositions.
Chitosans are biopolymers which belong to the group of hydrocolloids. Chemically, they are partly deacetylated chitins differing in their molecular weights which contain the followingxe2x80x94idealizedxe2x80x94monomer unit:
In contrast to most hydrocolloids, which are negatively charged at biological pH values, chitosans are cationic biopolymers under these conditions. The positively charged chitosans are capable of interacting with oppositely charged surfaces and are therefore used in cosmetic hair-care and body-care products and pharmaceutical preparations (cf. Ullmann""s Encyclopedia of Industrial Chemistry, 5th Ed., Vol. A6, Weinheim, Verlag Chemie, 1986, pages 231-332). Overviews of this subject have also been published, for example, by B. Gesslein et al. in HAPPI 27, 57 (1990), O. Skaugrud in Drug Cosm. Ind. 148, 24 (1991) and E. Onsoyen et al. in Seifen-xc3x96le-Fefte-Wachse 117, 633 (1991). Chitosans are produced from chitin, preferably from the shell residues of crustaceans which are available in large quantities as inexpensive raw materials. In a process described for the first time by Hackmann et al., the chitin is normally first deproteinized by addition of bases, demineralized by addition of mineral acids and, finally, deacetylated by addition of strong bases, the molecular weights being distributed over a broad spectrum. Corresponding processes are known, for example, from Makromol. Chem. 177, 3589 (1976) or French patent application FR 2701266 A. Preferred types are those which are disclosed in German patent applications DE 4442987 A1 and DE 19537001 A1 (Henkel) and which have an average molecular weight of 800,000 to 1,200,000 dalton, a Brookfield viscosity (1% by weight in glycolic acid) below 5,000 mPas, a degree of deacetylation of 80 to 88% and an ash content of less than 0.3% by weight. Besides the chitosans as typical cationic biopolymers, anionically or nonionically derivatized chitosans such as, for example, the carboxylation, succinylation or alkoxylation products described, for example, in German patent DE 3713099 C2 (L""Orxc3xa9al) and in German patent application DE 19604180 A1 (Henkel) are also suitable for the purposes of the invention. The percentage content of chitosans may be from 0 to 2% by weight and is preferably from 0.1 to 0.5% by weight, based on the final preparation.
Other suitable auxiliaries and additives, particularly for use in toothpastes, are humectants, for example sorbitol, glycerol or polyethylene glycols; consistency factors; deodorizing agents; swelling agents and binders, for example carboxymethyl cellulose or xanthan gum, agents active against diseases of the mouth and teeth; water-soluble fluorine compounds, for example sodium fluoride or sodium monofluorophosphate.
Basically, the percentage content of these auxiliaries and additives is not critical and depends upon the nature of the ultimate composition. Normally, it is from 5 to 98% by weight and preferably from 80 to 90% by weight, based on the final preparation.
A typical toothpastexe2x80x94another subject of the present inventionxe2x80x94has the following typical composition (water to 100% by weight):
(a) 0.1 to 20, preferably 0.6 to 5% by weight surfactant granules,
(b) 1 to 25, preferably 10 to 20% by weight abrasives and polishes,
(c) 0 to 65, preferably 10 to 45% by weight humectants,
(d) 0 to 2, preferably 0.1 to 0.5% by weight chitosans,
(e) 0 to 3, preferably 1 to 2% by weight flavorings and
(f) 0 to 5, preferably 1 to 3% by weight other auxiliaries, with the proviso that the quantities used add up to 100% by weight.

Method for producing surfactant granulates


Polyisobutenes are prepared by the continuous preparation process, by polymerizing isobutene in the presence of a catalyst comprising boron trifluoride and at least one cocatalyst in an inert organic solvent,

The present invention relates to a process for the continuous preparation of polyisobutenes by polymerizing isobutene in the presence of a catalyst comprising boron trifluoride and at least one cocatalyst in an inert organic solvent.
High molecular weight polyisobutenes having molecular weights up to several 100,000 Dalton have long been known. These polyisobutenes are generally prepared with the aid of Lewis acid catalysts, such as aluminum chloride, alkylaluminum chlorides or boron trifluoride and generally have not less than 10 mol % of terminal double bonds (vinylidene groups) and a molecular weight distribution (dispersity) of from 2 to 5.
The highly reactive polyisobutenes, which as a rule have average molar masses of from 500 to 5,000 Dalton and contain more than 60, preferably more than 80, mol % of terminal vinylidene groups, must be distinguished from these conventional polyisobutenes. In the context of the present application, terminal vinylidene groups or terminal double bonds are understood as meaning those double bonds whose position in the polyisobutene macromolecule is described by the formula,
where R is the polyisobutene radical shortened by two isobutene units. The type and the proportion of the double bonds present in the polyisobutene can be determined with the aid of 13C-NMR spectroscopy. Such highly reactive polyisobutenes are used as intermediates for the preparation of additives for lubricants and fuels, as described, for example, in DE-A 27 02 604. The terminal vinylidene groups have the highest reactivity, whereas the double bonds present further toward the interior of the macromolecules exhibit in the usual functionalization reactions only very little reactivity, if any at all, depending on their position in the macromolecule. The proportion of terminal vinylidene groups in the molecule is therefore the most important quality criterion for this type of polyisobutene.
Further quality criteria for polyisobutene are their average molecular weight and the molecular weight distribution (also referred to as dispersity) of the macromolecules contained in the polyisobutene. In general, polyisobutenes having average molecular weights (Mn) of from 500 to 50,000 Dalton are desirable. Molecular weights of from 500 to 5,000, preferably from 600 to 3,000, in particular from 700 to 2,500, Dalton are preferred for the preparation of polyisobutenes used as fuel additives, owing to their better efficiency.
Furthermore, a narrow molecular weight distribution of the polyisobutene molecules is desirable in order to reduce the proportion of undesired, relatively low molecular weight or high molecular weight polyisobutenes in the product produced and thus to improve its quality.
Various polymerization reactions of isobutene under catalysis by various boron trifluoride complexes are known.
EP 0 807 641 A2 describes a process for the preparation of highly reactive polyisobutene having an average molecular weight of more than 5,000 and up to 80,000 Dalton and containing at least 50 mol % of terminal vinylidene groups. The cationic polymerization of isobutene or isobutene-containing hydrocarbons is carried out in the liquid phase in the presence of boron trifluoride complex catalysts at below 0xc2x0 C. and from 0.5 to 20 bar, in one stage at a steady-state isobutene concentration of from 20 to 80% by weight. The boron trifluoride complex catalysts can be premolded before they are used or can be produced in situ in the polymerization reactor. The boron trifluoride concentration is from 50 to 500 ppm.
EP 0 628 575 A1 describes a process for the preparation of highly reactive polyisobutene containing more than 80 mol % of terminal vinylidene groups and having an average molecular weight of from 500 to 5,000 Dalton by cationic polymerization of isobutene or isobutene-containing hydrocarbons in the liquid phase in the presence of boron trifluoride and secondary alcohols of 3 to 20 carbon atoms. In addition to the separate preparation of the boron trifluoride complex with subsequent introduction into the reaction stream, production of the complex in situ is also proposed. The process is preferably operated with establishment of a steady-state monomer concentration in the reaction medium, which as a rule is set in the range from 0.2 to 50, preferably from 0.2 to 5, % by weight, based on the total polymerization mixture.
WO 99/31151 describes a process for the preparation of highly reactive low molecular weight polyisobutene, in which some of the boron trifluoride complex catalyst is recovered by separating the reactor discharge into a product-rich phase and a catalyst-rich phase and recycling the catalyst-rich phase to the polymerization reactor. However, this procedure makes it more difficult to carry out the reaction.
However, the reaction must be carried out precisely in order to ensure the product quality, in particular the uniformity of the molecular weight (i.e. for narrow molecular weight distribution) and a high content of vinylidene double bonds.
It is an object of the present invention to provide a continuous process for the preparation of polyisobutene having the generic features of the preamble of claim 1, in which the reaction can be carried out more precisely.
We have found that this object is achieved by a process for the continuous preparation of polyisobutene by polymerizing isobutene in the presence of a catalyst comprising boron trifluoride and at least one cocatalyst in an inert organic solvent,
a) a part of the reaction mixture obtained thereby being discharged continuously from the polymerization reactor,
b) the catalyst being separated from the discharge and/or being deactivated in the discharge and,
c) the solvent and any unconverted isobutene being separated from the discharge and recycled to the polymerization reactor,
wherein the recycled solvent and, if present, the isobutene are subjected to a wash with water before the recycling to the polymerization reactor and, if required, are then dried.
The separation of the solvent and of any unconverted isobutene from the discharge is effected as a rule by distilling off the solvent, isobutene and other volatile components also distilling off. As a result of the novel washing of the solvent with water before the recycling, the residues of water-soluble cocatalysts and traces of fluorine-containing decomposition products still present are removed in a simple manner and with high efficiency.
The washing of the solvent before recycling can be carried out in one stage or a plurality of stages. In a one-stage procedure, as a rule the solvent separated from the discharge is mixed with a sufficient amount of water in a mixer and a phase separation is then carried out in a separation vessel. For the multistage wash, these operations can be repeated several times in the manner of a cascade. Preferably, the multistage wash is carried out in an extraction column.
For washing the solvent, as a rule the solvent/water ratio of from 20:1 to 1:2, in particular from 10:1 to 1:1 (v/v) is chosen. In a one-stage wash, the ratio of solvent to water is particularly preferably about 1:1 (v/v); in a multistage wash or in the extraction using an extraction column, the solvent/water ratio is preferably not less than 2:1 and preferably from 2:1 to 1:10.
The wash is carried out as a rule at from 5 to 80xc2x0 C., preferably from 10 to 50xc2x0 C. A wash under superatmospheric pressure is also suitable.
The wash water produced during washing of the solvent (and of any unconverted isobutene) can be removed as wastewater. Since the pollution of the wash water with residues of water-soluble cocatalyst and fluorine-containing decomposition products is comparatively low, the wash water can advantageously be reused in the novel process before it is disposed of as wastewater. The wash water is, for example, suitable for deactivating the catalyst in the reaction discharge with simultaneous extraction of the catalyst decomposition products from the reaction discharge, as described in more detail further below. This second use of the wash water leads on the one hand to a saving of fresh water and a reduction in the amount of wastewater in the total process. A further advantage is the reduction of solvent and isobutene losses, which are attributable to the fact that the solvent and isobutene are slightly soluble in water. Since the wash water is already saturated with solvent (and possibly isobutene) after the washing of the recycled solvent (and any isobutene), there is no further passage of solvent and any isobutene into the wash water phase in the catalyst deactivation stage, so that the losses of solvent and any isobutene via the wastewater are reduced.
After the solvent has been separated off, the residue which contains the desired polyisobutene is worked up in a conventional manner. For this purpose, the residue is subjected, for example, to further washing stages with water or alcoholic solvents, e.g. methanol, or solvent/water mixtures, in order to remove catalyst residues. Traces of solvent and of water as well as volatile oligomers of isobutene are removed by conventional methods, for example by evaporation in an annular gap evaporator or by extrudate devolatilization.
The novel process is a continuous process. Measures for continuously polymerizing isobutene in the presence of catalysts comprising boron trifluoride and at least one cocatalyst in inert organic solvents to give polyisobutene are known per se. In a continuous process, a part of the reaction mixture formed in the polymerization reactor is discharged continuously. Of course, an amount of starting material which corresponds to the discharge is fed continuously to the polymerization reactor. The ratio of the amount of substance present in the polymerization reactor to the amount which is discharged is determined by the circulation/feed ratio, which in the continuous polymerization of isobutene to polyisobutene is as a rule from 1000:1 to 1:1, according to the invention preferably from 500:1 to 5:1, in particular from 50:1 to 200:1 (v/v). The average residence time of the isobutene to be polymerized in the polymerization reactor may be from 5 seconds to several hours. Residence times of from 1 to 30, in particular from 2 to 20, minutes are preferred. The polymerization of the isobutene is effected in the reactors customary for the continuous polymerization, such as stirred kettles, tubular reactors, tube-bundle reactors and loop reactors, loop reactors, i.e. tube (-bundle) reactors having stirred kettle characteristics, being preferred. Tubular reactors having tube cross-sections which lead to turbulence in sections are particularly advantageous.
The novel process is carried out as a rule at a polymerization temperature of from xe2x88x9260xc2x0 C. to +40xc2x0 C., preferably below 0xc2x0 C., particularly preferably from xe2x88x9250xc2x0 C. to xe2x88x9240xc2x0 C., especially from xe2x88x9210xc2x0 C. to xe2x88x9230xc2x0 C. The heat of polymerization is correspondingly removed with the aid of a cooling apparatus. This may be operated, for example, with liquid ammonia as coolant. Another possibility for removing the heat of polymerization is by evaporative cooling. The heat liberated is removed by evaporating the isobutene and/or other readily volatile components of the isobutene feedstock or any readily volatile solvent. The novel polymerization process is preferably carried out under isothermal conditions, i.e. the temperature of the liquid reaction mixture in the polymerization reactor has a constant value and changes only to a small extent, if at all, during the operation of the reactor.
The concentration of the isobutene in the liquid reaction phase is as a rule from 0.2 to 50, preferably from 0.5 to 20, in particular from 1 to 10, % by weight, based on the liquid reaction phase. In the preparation of polyisobutenes having number-average molecular weights Mn of from 500 to 5,000 Dalton, an isobutene concentration of from 1 to 20, in particular from 1.5 to 15, % by weight is preferably employed. In the preparation of polyisobutenes having a number-average molecular weight Mn above 5,000 Dalton, an isobutene concentration of from 4 to 50% by weight is preferably employed.
The isobutene conversion can in principle be established as desired. However, it is self evident that the cost-efficiency of the process is doubtful at very low isobutene conversions whereas the danger of the double bond shifts increases and shorter reaction times and improved heat removal are required at very high isobutene conversions of more than 99%. For these reasons, the isobutene conversion is usually carried out to values in the range from 20 to 99%. Isobutene conversions from 70 to 98% are particularly preferred.
Suitable feedstocks for the novel process are isobutene itself and isobutene-containing C4-hydrocarbon streams, for example refined C4 fractions, C4 cuts from isobutene dehydrogenation and C4 cuts from steam crackers and FCC crackers (FCC: Fluid Catalysed Cracking), provided that they have been substantially freed from 1,3-butadiene contained therein. C4-hydrocarbon streams suitable according to the invention contain, as a rule, less than 500 ppm, preferably less than 200 ppm, of butadiene. The presence of 1-butene and cis- and trans-2-butene is substantially noncritical for the novel process and does not lead to loss of selectivity. Typically, the concentration in the C4-hydrocarbon streams is from 40 to 60% by weight. When C4-cuts are used as feedstock, the hydrocarbons other than isobutene assume the role of an inert solvent. The isobutene feedstock may contain small amounts of contaminants, such as water, carboxylic acids or mineral acids without resulting in critical reductions in yield or in selectivity during the polymerization. This results in lower alcohol/ether consumption, which changes the abovementioned molar ratios in favor of BF3. It is expedient to avoid an accumulation of these impurities in the plant, by removing such pollutants, for example by adsorption on solid adsorbents, such as active carbon, molecular sieves or ion exchangers, from the isobutene-containing feedstock.
Solvents or solvent mixtures which are suitable for the novel process are those which are inert to the reagents used. Suitable solvents are, for example, saturated hydrocarbons, such as butane, pentane, hexane, heptane or octane, e.g. n-hexane, isooctane, cyclobutane or cyclopentane, halogenated hydrocarbons, such as methyl chloride, dichloromethane or trichloromethane, and mixtures of the abovementioned compounds. Before they are used in the novel process, the solvents are preferably freed from impurities, such as water, carboxylic acids or mineral acids, for example by adsorption on solid adsorbents, such as active carbon, molecular sieves or ion exchangers.
In the novel process, the polymerization is carried out in the presence of boron trifluoride complex catalysts. These are understood as meaning catalysts comprising boron trifluoride and at least one cocatalyst. Suitable cocatalysts are as a rule oxygen-containing compounds. Suitable oxygen-containing compounds in addition to water are organic compounds of up to 30 carbon atoms which contain at least one oxygen atom bonded to carbon. Examples of these are C1-C10-alkanols and cycloalkanols, C2-C10-diols, C1-C20-carboxylic acids, C4-C12-carboxylic anhydrides and C2-C20-dialkyl ethers. Preferred among these are monohydric alkanols of from 1 to 20, in particular 1 to 4, carbon atoms, which, if required, can be used together with the C1-C20-dialkyl ethers. Molar ratios of boron trifluoride to oxygen-containing compound of from 1:1 to 1:10, in particular from 1:1.1 to 1:5, especially from 1:1.2 to 1:2.5 are preferred according to the invention in boron trifluoride complex catalysts. The BF3 concentration in the reactor will as a rule vary in the range from 0.01 to 1, in particular from 0.02 to 0.7, especially from 0.03 to 0.5, % by weight, based on the liquid reaction phase.
In the novel process, the oxygen-containing compound in the boron trifluoride complex catalyst particularly preferably comprises at least one monohydric, secondary alcohol A of 3 to 20 carbon atoms. Examples of suitable secondary alcohols are the following: isopropanol, 2-butanol, and furthermore sec-pentanols, sec-hexanols, sec-heptanols, sec-octanols, sec-nonanols, sec-decanols or sec-tridecanols. In addition to monohydric, secondary alcohols, it is also possible to use (poly)etherols of propene oxide and of butene oxide according to the invention. 2-Butanol and in particular isopropanol are preferably used.
The boron trifluoride complexes can be preformed in separate reactors before they are used in the novel process, temporarily stored on their formation and metered into the polymerization apparatus according to demand. The BF3 complex catalysts are prepared as a rule by passing BF3 into the cocatalyst or into a solution of the cocatalyst in one of the abovementioned inert organic solvents at from xe2x88x9260 to +60xc2x0 C., preferably from xe2x88x9230 to +20xc2x0 C. The activity of the catalyst can be manipulated by adding further cocatalysts.
In another, preferred variant, the boron trifluoride complexes are produced in situ in the polymerization apparatus. In this procedure, the respective cocatalyst is, if required, fed together with a solvent into the polymerization apparatus and boron trifluoride is dispersed in the required amount in this mixture of the reactants. Here, the boron trifluoride and the cocatalysts react to give the boron trifluoride complex. Instead of an additional solvent, isobutene or the reaction mixture comprising unconverted isobutene and polyisobutene can act as a solvent in the in situ production of the boron trifluoride catalyst complex.
In a preferred embodiment, first a complex of dialkyl ether B and BF3 is prepared separately or in the solvent feed to the reactor and only thereafter combined with the secondary alcohol A in the complex feed or solvent feed to the reactor or in the reactor itself. Consequently, the energy of the complex formulation can be removed without harmful byproduct formation during the production of the alcohol complex. Moreover, this procedure permits the simple manipulation of the catalyst activity via the ratio of boron trifluoride to alcohol.
Gaseous boron trifluoride is expediently used as raw material for the preparation of the boron trifluoride complexes, it being possible to use technical-grade boron trifluoride still containing small amounts of sulfur dioxide and SiF4 (purity: 96.5% by weight), but preferably high-purity boron trifluoride (purity: 99.5% by weight).
The reaction mixture discharged from the polymerization reactor still contains a polymerizable isobutene, BF3 and cocatalyst. As a rule, the polymerization therefore also continues in the discharge. As a result of this, the polyisobutene formed in the polymerization reactor may change in a disadvantageous manner with respect to molecular weight, molecular weight distribution and terminal group content. To prevent further reaction, the polymerization is therefore usually stopped by deactivating the catalyst. The deactivation can be effected, for example, by adding water, alcohols, acetonitrile, ammonia or aqueous solutions of mineral bases or by passing the discharge into one of the abovementioned media. The deactivation is preferably carried out using water, preferably at from 1 to 60xc2x0 C. (water temperature). During the deactivation with water the deactivation in the narrow sense of the word (by formation of a catalytically inactive BF3-water complex) is accompanied by hydrolysis of the boron trifluoride to water-soluble hydrolysis products, such as boric acid and hydrogen fluoride, which pass over into the aqueous phase and are thus removed for the most part from the orgaic phase. After phase separation into an organic phase and into an aqueous phase, if required, the solvent is separated from the polyisobutene in the discharge thus deactivated, by evaporation and condensation or by controlled distillation, and is further treated in the manner described above.
In a preferred embodiment of the novel process, the boron trifluoride complex catalyst is substantially separated from the discharge and recycled to the polymerization reaction. The separation and recycling of the catalyst from the discharge of the polymerization reaction is disclosed in WO 99/31151, which is hereby incorporated in full by reference. For separation of the catalyst from the discharge, preferably boron trifluoride complex catalysts having limited solubility are used and/or the reaction mixture is cooled to, for example, from 5 to 30, preferably from 10 to 20, Kelvin below the reactor temperature.
On separating the catalyst from the reactor discharge, it is advisable to reduce the isobutene concentration of the discharge to below 2, preferably 1, in particular below 0.5, % by weight, based on the discharge, beforehand. As a rule, the reactor discharge is therefore subjected to a further polymerization stage before the catalyst is separated off. The multistage isobutene polymerization described in WO 96/40808, in which residual isobutene of the main reactor is consumed down to about 0.5% in the downstream reactor, is a preferred procedure for the novel process. Preferably, this second polymerization stage is operated at the same temperature as the first polymerization stage or at a lower polymerization temperature than the first polymerization stage. As a rule, the temperature difference is from 0 to 20 Kelvin, preferably from 0 to 10 Kelvin.
The downstream reaction, in particular the cooled downstream reaction, results in more complex separating out. The solubility of the complex decreases at least by a power of 10, and in particular if the temperature reduction is also effected. Here, the catalyst is obtained in the form of finely divided droplets, which as a rule are rapidly transformed into a coherent phase. The complex droplets or the coherent phase have or has a substantially high density than the polymer solution. As a rule, they can therefore be separated from the polymer-rich, catalyst-poor product phase with the aid of precipitators, separators or other collecting containers. If the catalyst is obtained only in the form of very finely divided droplets which are difficult to separate off, the conventional measures for droplet enlargement, for example coalescing filters, can be used. Methods for this purpose are described, for example, in WO 99/31151.
The formation of a coherent catalyst phase is however not essential for recycling the catalyst. A phase in which the complex is still distributed in disperse form can, if required, also be fed to the reactor. The concentrated and/or isolated catalyst is then fed to the polymerization as a rule without further purification or, in the case of a multistage polymerization, as a rule to the first polymerization stage. Since as a rule there are certain reductions in activity on isolating the catalyst, said reductions are compensated by adding small amounts of catalyst, for example from 1 to 30, preferably from 3 to 20, in particular from 5 to 10, % by weight, based on the amounts of complex which are required in a straight path. As a rule, it is therefore possible to recycle from 40 to 95%, preferably from 70 to 90%, of the catalyst.
The polymer-rich product phase separated off is generally homogeneous and contains only small amounts of soluble catalyst fractions. These are deactivated in the manner described above, preferably with water. Thereafter, the solvent is separated from the product in the manner described above and is subjected to the novel wash. In this embodiment, it is also possible to absorb the residues of the dissolved complex on nitrile-containing materials, for example according to EP-A-791 557, or nitrile-modified silica gel.
The novel process enables good control of the isobutene polymerization and permits specific preparation of highly reactive polyisobutenes having a number-average molecular weight Mn of from 500 to 50,000 Dalton and containing at least 60 mol % of terminal vinylidene groups. The novel process has proven particularly useful in the preparation of polyisobutenes having a number-average molecular weight Mn of from 500 to 5,000, in particular from 700 to 2,500, and containing at least 80 mol %, based on all terminal groups, of vinylidene groups. At the same time, a better molecular uniformity of the polyisobutene, characterized by the ratio of weight average molecular weight {overscore (M)}w to number average molecular weight Mn (=dispersity D=Mw/Mn), is achieved. Typically, the novel process enables production of polyisobutenes in the stated molecular weight range with an Mw/Mnxe2x89xa62.5, preferablyxe2x89xa62.0, and in particularxe2x89xa61.8. In contrast to the prior art processes, these values are also achieved in the case of solvent recycling. Furthermore, in contrast to the prior art processes, the content of reactive terminal groups does not decrease below 60, preferably 80, mol % on recycling the solvent. In particular, the process makes it possible to maintain the abovementioned quality features for polyisobutene having molecular weights of from 500 to 5,000. This presumably is due to better control of the polymerization, which has possibly been complicated to date by catalyst traces and/or cocatalyst traces in the recycled solvent.

Method for producing highly reactive polyisobutenes

Abstract: b) the catalyst being separated from the discharge and/or being deactivated in the discharge, and

Abstract: wherein the recycled solvent and, if present, the isobutene are subjected to a wash with water before recycling to the polymerization reactor and are then dried.


A pharmaceutical composition comprises at least one inhibitor of lipases, preferably an inhibitor of gastrointestinal and pancreatic lipases, such as orlistat, at least one surfactant, and at least one dispersant.

1. Field
The present invention relates to pharmaceutical compositions comprising lipase inhibitors.
2. Description
Examples of lipase inhibitors include lipstatin and orlistat. The latter is also known as tetrahydrolipstatin or THL and is derived from a natural product excreted by Streptomyces toxytricini. This class of compounds was found to exhibit in vitro as well as in vivo activity against various lipases, such as lingual lipase, pancreatic lipase, gastric lipase, and carboxylester lipase. Its use for the control or prevention of obesity and hyperlipidemia is described, for instance, in U.S. Pat. No. 4,598,089.
Orlistat is currently administered at doses of 120 mg per meal and dosing is independent of the body mass of the human subject. Orlistat acts locally in the gastrointestinal (GI) tract and prevents lipase from digesting triglycerides and subsequently inhibits the formation of absorbable lipid degradation products. For this reason, systemic availability of the lipase inhibitors is not required and, instead, local residence in the gastrointestinal tract is preferred.
Lipase inhibitor compositions currently administered inhibit around 30% of fat absorption after consumption of a mixed meal; an increase of the lipase inhibitors concentration in the pharmaceutical composition does not increase its clinical efficacy while the intensity of local side effects increases.
Anal leakage of oil (oily spotting) is an adverse effect that is occasionally observed in patients treated with lipase inhibitors. This phenomenon reflects physical separation of some liquid unabsorbed dietary fat from the bulk of solids in the lower large intestine.
There has been a long felt need for lipase inhibitor compositions that improve the clinical efficacy and/or potency of the inhibitor itself, and/or to minimize or suppress the above mentioned disadvantages.

Pharmaceutical compositions containing lipase inhibitors