My cat and my kitten fight a lot. What should I do?

My family and I have had Leo, my male cat, since he was one day old. His mom abandoned him, so my family took him in and raised him. He never really acted like a cat before. We think he thinks he is a human. He also has mood issues, which the vet said is normal for human raised cats. He was our only inside cat for 2 years. In November one of our outside kittens came down with severe ear mites and we almost lost her. She is now an inside cat too. Until about January Leo was afraid of Squeaky. He would hid from her and hiss at her. Now they are best friends and you will hardly see one without the other. Leo is laid back, but Squeaky is extremely hyper active. She is only playing with him, but it will make him mad after awhile and he will attack her and make her cry. He is a big boy close to 15 pounds, but squeaky isnt even 5 pounds. She will attack him until she hurts him by biting him and stuff too. They are best friends until she makes him mad. What should I do when she starts making him mad? I tried locking one of them up in my bedroom with me, but they will both sit by the door and cry for each other. But when I open the door they start fighting again. Has anyone else ever had cats that did this?